Bicyclic-substituted amines as histamine-3 receptor ligands

ABSTRACT

Compounds of formula (I) 
                         
are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 12/196,124, filed Aug. 21, 2008, which is a divisionalapplication of U.S. patent application Ser. No. 11/418,699, filed May 5,2006, and issued as U.S. Pat. No. 7,456,196 on Nov. 25, 2008, which is adivisional of U.S. patent application Ser. No. 10/689,735, filed Oct.22, 2003, and issued as U.S. Pat. No. 7,153,889 on Dec. 26, 2006, whichclaims the benefit of U.S. Provisional Patent Application Ser. No.60/425,376, filed Nov. 12, 2002, all of which are hereby incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to bicyclic-substituted amine compounds,compositions comprising such compounds, methods for making thecompounds, and methods of treating conditions and disorders using suchcompounds and compositions.

2. Description of Related Technology

Histamine is a well-known modulator of neuronal activity. At least fourtypes of histamine receptors have been reported in the literature,typically referred to as histamine-1, histamine-2, histamine-3, andhistamine-4. The class of histamine receptor known as histamine-3receptors is believed to play a role in neurotransmission in the centralnervous system.

The histamine-3 (H₃) receptor was first characterized pharmacologicallyon histaminergic nerve terminals (Nature, 302:832-837 (1983)), where itregulates the release of neurotransmitters in both the central nervoussystem and peripheral organs, particularly the lungs, cardiovascularsystem and gastrointestinal tract. H₃ receptors are thought to bedisposed presynaptically on histaminergic nerve endings, and also onneurons possessing other activity, such as adrenergic, cholinergic,serotoninergic, and dopaminergic activity. The existence of H₃ receptorshas been confirmed by the development of selective H₃ receptor agonistsand antagonists ((Nature, 327:117-123 (1987); Leurs and Timmerman, ed.“The History of H₃ Receptor: a Target for New Drugs,” Elsevier (1998)).

The activity at the H₃ receptors can be modified or regulated by theadministration of H₃ receptor ligands. The ligands can demonstrateantagonist, agonist or partial agonist activity. For example, H₃receptors have been linked to conditions and disorders related to memoryand cognition processes, neurological processes, cardiovascularfunction, and regulation of blood sugar, among other systemicactivities. Although various classes of compounds demonstrating H₃receptor-modulating activity exist, it would be beneficial to provideadditional compounds demonstrating activity at the H₃ receptors that canbe incorporated into pharmaceutical compositions useful for therapeuticmethods.

SUMMARY OF THE INVENTION

The invention is directed to substituted amines and, more particularly,bicyclic-substituted amines. Accordingly, one aspect of the inventionrelates to compounds of formula (I):

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

Y, and Y′ are each independently selected from the group consisting ofCH, CF, and N;

X, X′, Z, and Z′ are each independently C or N;

one of R₁ and R₂ is selected from the group consisting of halogen,cyano, and L₂R₆;

the other of R₁ and R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, andthioalkoxy, provided that R₂ is absent when Z′ is N;

R₃ is absent when X′ is N or R₃ is selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;

R_(3a) is absent when Z is N or R_(3a) is selected from the groupconsisting of hydrogen, methyl, alkoxy, halogen, and cyano;

R_(3b) is absent when X is N or R_(3b) is selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, andthioalkoxy;

R₄ and R₅ are each independently selected from the group consisting ofalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyland (NR_(A)R_(B))alkyl, or R₄ and R₅ taken together with the nitrogenatom to which each is attached form a non-aromatic ring of the formula:

R₆ is selected from the group consisting of aryl, heteroaryl,heterocycle, and cycloalkyl;

R₇, R₈, R₉, and R₁₀ at each occurrence are each independently selectedfrom the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, andalkyl; or one of the pair R₇ and R₈ or the pair R₉ and R₁₀ is takentogether to form a C₃-C₆ ring, wherein 0, 1, or 2 heteroatoms selectedfrom O, N, or S replace a carbon atom in the ring;

R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from the groupconsisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;

Q is selected from the group consisting of a bond, O, S, and NR₁₅;

L is —[C(R₁₆)(R₁₇)]_(n)— or —[C(R₁₆)(R₁₇)]_(p)O—;

L₂ is a bond or L₂ is selected from the group consisting of —O—,—C(═O)—, —S—, —[C(R₁₈)(R₁₉)]_(q)—, —O—[C(R₁₈)(R₁₉)]_(q)—, —NH— and—N(alkyl)-;

R₁₅ is selected from the group consisting of hydrogen, alkyl, acyl,amido, and formyl;

R₁₆ and R₁₇ at each occurrence are independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, and fluoro;

R₁₈ and R₁₉ at each occurrence are each independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;

R_(x) and R_(y) at each occurrence are each independently selected fromthe group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino,dialkylamino, and fluoro, or one of R_(x) or R_(y) represents a covalentbond when taken together with R_(x) or R_(y) on an adjacent carbon atomsuch that a double bond is represented between the adjacent carbonatoms;

m is an integer from 1 to 5;

n is an integer from 1 to 6;

p is an integer from 2 to 6; and

q is an integer from 1 to 4;

wherein 0, 1, or 2 of X, X′, Y, Y′, Z, and Z′ can be nitrogen; providedthat R₃ is absent when X′ is N; R_(3a) is absent when Z is N; R₂ isabsent when Z′ is N; and R_(3b) is absent when X is N.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to H₃ receptor activity.

Yet another aspect of the invention relates to a method of selectivelymodulating H₃ receptor activity. The method is useful for treatingand/or preventing conditions and disorders related to H₃ receptormodulation in mammals. More particularly, the method is useful forconditions and disorders related to memory and cognition processes,neurological processes, cardiovascular function, and body weight.

Processes for making compounds of the invention also are contemplated.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein, means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein, means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.

The term “alkoxysulfonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylamino” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a NH group.Representative examples of alkylamino include, but are not limited to,methylamino, ethylamino, isopropylamino, and butylamino.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amido” as used herein, means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “amino” as used herein, means a —NH₂ group. The term “aryl” asused herein, means a monocyclic aromatic ring system. Representativeexamples of aryl include, but are not limited to, phenyl.

The aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or5 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, cycloalkylcarbonyl, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy,NR_(A)R_(B), and (NR_(A)R_(B))sulfonyl.

The term “arylalkoxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group,as defined herein. Representative examples of arylalkoxy include, butare not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and5-phenylpentyloxy.

The term “arylalkoxycarbonyl” as used herein, means an arylalkoxy group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “carbonyl” as used herein, means a —C(═O)— group.

The term “carboxy” as used herein, means a —CO₂H group, which may beprotected as an ester group —CO₂-alkyl.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkenyl” as used herein, means a cyclic hydrocarboncontaining from 3 to 8 carbons and containing at least one carbon-carbondouble bond formed by the removal of two hydrogens. Representativeexamples of cycloalkenyl include, but are not limited to,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and3-cyclopenten-1-yl.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The cycloalkyl groups of the invention are substituted with 0, 1, 2, 3,or 4 substituents selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, alkynyl,amido, carboxy, cyano, ethylenedioxy, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, methylenedioxy, thioalkoxy, and—NR_(A)R_(B).

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “cycloalkylcarbonyl” as used herein, means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.

The term “dialkylamino” as used herein, means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom. Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, butylmethylamino.

The term “ethylenedioxy” as used herein, means a —O(CH₂)₂O— groupwherein the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through one carbon atom forming a five-memberedring or the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through two adjacent carbon atoms forming asix-membered ring.

The term “fluoro” as used herein means —F.

The term “fluoroalkyl” as used herein, means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative example of fluoroalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring wherein 1, 2, 3, or 4 heteroatoms are independentlyselected from nitrogen, oxygen, or sulfur, or a tautomer thereof.Examples of such rings include, but are not limited to, a ring whereinone carbon is replaced with an O or S atom; one, two, or three N atomsarranged in a suitable manner to provide an aromatic ring, or a ringwherein two carbon atoms in the ring are replaced with one O or S atomand one N atom. The heteroaryl groups are connected to the parentmolecular moiety through a carbon or nitrogen atom. Representativeexamples of heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridinonyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl orthiophenyl, triazinyl, and triazolyl. Specific heteroaryl groupsinclude, but are not limited to, 2H-pyridazin-3-one-2-yl.

The heteroaryl groups of the invention are substituted with 0, 1, 2, 3,or 4 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, thioalkoxy, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “heterocycle,” as used herein, refers to a three-, four-,five-, six-, seven-, or eight-membered ring containing one, two, orthree heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. Rings containing at least four members canbe saturated or unsaturated. For example, the four- and five-memberedring has zero or one double bond. The six-membered ring has zero, one,or two double bonds. The seven- and eight-membered rings have zero, one,two, or three double bonds. The heterocycle groups of the invention canbe attached to the parent molecular moiety through a carbon atom or anitrogen atom. Representative examples of nitrogen-containingheterocycles include, but are not limited to, azepanyl, azetidinyl,aziridinyl, azocanyl, morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, and thiomorpholinyl.Representative examples of non-nitrogen containing heterocycles include,but are not limited to, tetrahydrofuryl and tetrahydropyranyl.

The heterocycles of the invention are substituted with 0, 1, 2, 3, or 4substituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylsulfonyl, alkynyl, amido, arylalkyl, arylalkoxycarbonyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, oxo, thioalkoxy, —NR_(A)R_(B), and(NR_(A)R_(B))sulfonyl.

The term “hydroxy” as used herein means a —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” means a substituent which protectshydroxyl groups against undesirable reactions during syntheticprocedures. Examples of hydroxy-protecting groups include, but are notlimited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl,2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, methylene acetal, acetonide benzylidene acetal,cyclic ortho esters, methoxymethylene, cyclic carbonates, and cyclicboronates. Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with a base,such as triethylamine, and a reagent selected from an alkyl halide,alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate,aryldialkylsilyltriflate, or an alkylchloroformate, CH₂I₂, or adihaloboronate ester, for example with methyliodide, benzyl iodide,triethylsilyltriflate, acetyl chloride, benzylchloride, ordimethylcarbonate. A protecting group also may be appended onto ahydroxy group by reaction of the compound that contains the hydroxygroup with acid and an alkyl acetal.

The term “imino” as defined herein means a —C(═NH)— group.

The term “mercapto” as used herein, means a —SH group.

The term “methylenedioxy” as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “—NR_(A)R_(B)” as used herein, means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are independently selected from hydrogen,alkyl, acyl and formyl. Representative examples of —NR_(A)R_(B) include,but are not limited to, amino, dimethylamino, methylamino, acetylamino,and acetylmethylamino.

The term “(NR_(A)R_(B))alkyl” as used herein, means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to,2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(amino)ethyl,2-(ethylmethylamino)ethyl, and the like.

The term “(NR_(A)R_(B))carbonyl” as used herein, means an alkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “(NR_(A)R_(B))sulfonyl” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “nitro” as used herein means a —NO₂ group.

The term “nitrogen protecting group” as used herein, means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl trifilate, a dialkyl anhydride, for example as represented by(alkyl-O)₂C═O, a diaryl anhydride, for example as represented by(aryl-O)₂C═O, an acyl halide, an alkylchloroformate, or analkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetylchloride, benzoylchloride, benzylbromide,benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,pivaloylchloride, (tert-butyl-O—C═O)₂O, trifluoroacetic anhydride, andtriphenylmethylchloride.

The term “hydroxy protecting group” or “O-protecting group” or “oxygenprotecting group” means a substituent which protects hydroxy groupsagainst undesirable reactions during synthetic procedures. Examples ofhydroxy protecting groups include, but are not limited to, substitutedmethyl ethers, for example, methoxymethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, andtriphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, forexample, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl;cyclic acetals and ketals, for example, methylene acetal, acetonide, andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates.

The term “oxo” as used herein means (═O).

The term “sulfonyl” as used herein means a —S(O)₂— group.

The term “thioalkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

As used herein, the term “antagonist” encompasses and describescompounds that prevent receptor activation by an H₃ receptor agonistalone, such as histamine, and also encompasses compounds known as“inverse agonists”. Inverse agonists are compounds that not only preventreceptor activation by an H₃ receptor agonist, such as histamine, butalso inhibit intrinsic H₃ receptor activity.

Compounds of the Invention

Compounds of the invention can have the general formula (I) as describedabove.

As previously described, Y, and Y′ each can be CH, CF, or N, and X, X′,Z, and Z′ each can be independently selected from C or N.

R₁ can be halogen, cyano, or L₂R₆, wherein L₂ is selected from the groupconsisting of a bond, —O—, —C(═O)—, —S—, —[C(R₁₈)(R₁₉)]_(q)—, as definedherein, —O—[C(R₁₈)(R₁₉)]_(q)—, as defined herein, —NH—, and —N(alkyl)-,and R₆ is selected from the group consisting of aryl, heteroaryl,heterocycle, and cycloalkyl.

Typically, the substituent for R₁ is selected from bromo, cyano, orL₂R₆. Specific examples of groups for R₁ wherein the substituent ishalogen or cyano include, but are not limited to, bromo and cyano.

Preferably L₂ is selected from a bond, —O—, —C(═O)—, —S—, or—[C(R₁₈)(R₁₉)]_(q)—. Specific groups for L₂ include, but are not limitedto, —CH(OH)—, —C(═O)—, and where L₂ is a bond.

L₂ as a bond is most preferred. Preferred groups for R₆ are aryl,heteroaryl, and cycloalkyl. The aryl, heteroaryl, and heterocyclicgroups can be unsubstituted or substituted, for example as described inthe Definition of Terms.

Examples of aryl groups for R₆ can include, but are not limited to,phenyl. The phenyl groups can be substituted with at least 0, 1, or 2substituents. Preferred substituents for aryl are cyano, halogen,—NR_(A)R_(B), alkoxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl,cycloalkylcarbonyl, thioalkoxy, alkylsulfonyl, and haloalkyl. The morepreferred substituent is cyano. Specific examples include, but are notlimited to, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl,3,5-difluorophenyl, 4-(dimethylamino)phenyl, 4-ethoxyphenyl,3-fluorophenyl, 4-fluorophenyl, 3-hydroxymethylphenyl,4-(1-hydroxy-1-methylethyl)phenyl, 3-(methylcarbonyl)phenyl,4-(methylcarbonyl)phenyl, 4-(methylsulfanyl)phenyl,4-(methylsulfonyl)phenyl, 4-methoxyphenyl,4-(cyclopropylcarbonyl)phenyl, 4-(methoxycarbonyl)phenyl, and4-(trifluoromethyl)phenyl.

One particular embodiment is a compound of formula (I) wherein R₁ isL₂R₆, L₂ is a bond and R₆ is aryl wherein the aryl is phenyl substitutedwith 0, 1, or 2 substituents selected from the group consisting ofcyano, halogen, —NR_(A)R_(B), alkoxy, hydroxyalkyl, alkylcarbonyl,alkoxycarbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, andthioalkoxy.

Specific heteroaryl groups for R₆ can include, but are not limited to,furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinonyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl,thienyl, triazinyl, and triazolyl. Specific heteroaryl groups for theinvention include, but are not limited to, for example, furan-3-yl,pyrazin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrrol-2-yl,1,3-thiazol-2-yl, 1,3-thiazol-5-yl, thiophen-3-yl, and thiophen-2-yl.Also included as heteroaryl groups of the invention are2H-pyridazin-3-one, particularly 2H-pyridazin-3-one-2-yl, and1H-pyridin-2-one, particularly 1H-pyridin-2-one-1-yl. A preferredheteroaryl group is 2H-pyridazin-3-one-2-yl.

The heteroaryl groups can be substituted with at least 0, 1, 2, or 3substituents. Preferred substituents for the heteroaryl groups are—NR_(A)R_(B), halogen, alkyl, cyano, alkoxyimino, alkoxycarbonyl,(NR_(A)R_(B))carbonyl, alkylcarbonyl, haloalkyl, and alkoxy. Specificexamples of substituted heteroaryl groups for the invention include, butare not limited to, 2-aminopyrimidin-5-yl, 3-bromoisoxazol-5-yl,3-chloropyridin-4-yl, 6-chloropyridin-3-yl, 5-cyanopyridin-3-yl,3-cyano-2,6-dimethylpyridin-3-yl, 2,6-dichloropyridin-3-yl,2,6-dimethylpyridin-3-yl, 1,3-dimethylpyrazol-4-yl,1,5-dimethylpyrazol-4-yl, 3,5-dimethylpyrazol-4-yl, 5-cyanothien-2-yl,2-cyanopyrimidin-5-yl, 2,5-dimethylfur-3-yl, 3,5-dimethylthien-2-yl,5-(ethoxyiminomethyl)thien-2-yl, 6-fluoropyridin-3-yl,2,6-difluoropyridin-3-yl, 4-(ethoxycarbonyl)-3-methylisoxazol-5-yl,3,5-dimethylisoxazol-4-yl, 3-(ethoxycarbonyl)isoxazol-5-yl,3-methylpyrazin-2-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,2,6-dimethyl-5-(aminocarbonyl)pyridin-3-yl,2,6-dimethyl-5-(methylcarbonyl)pyridin-3-yl,4-hydroxy-2-(trifluoromethyl)pyridin-3-yl,6-(methylcarbonyl)pyridin-2-yl, 2,4-dimethoxypyrimidin-5-yl,6-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, 2,4-dimethylthiazol-5-yl,2,4-dimethyloxazol-5-yl, 6-chloropyridazin-3-yl,6-methoxypyridazin-3-yl, 6-methylpyridazinonyl, 4-methylpyridinonyl, and1-(tert-butoxycarbonyl)pyrrol-2-yl.

A particular embodiment is a compound of formula (I) wherein R₁ is L₂R₆,L₂ is a bond, and R₆ is selected from the group consisting of furyl,isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyridinonyl,pyridazinyl, pyridazinonyl, pyrimidinyl, pyrrolyl, thiazolyl, andthienyl, substituted with 0, 1, 2, or 3 substituents selected from thegroup consisting of —NR_(A)R_(B), halogen, alkyl, cyano, alkoxyimino,alkoxycarbonyl, (NR_(A)R_(B))carbonyl, alkylcarbonyl, haloalkyl, andalkoxy.

Heterocycle groups for R₆ can include, but are not limited to, azepanyl,azetidinyl, aziridinyl, azocanyl, dihydrothiazolyl, morpholinyl,piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, andtetrahydropyridinyl, as well as non-nitrogen containing heterocycles,for example, tetrahydrofuryl and tetrahydropyranyl. Heterocycles can besubstituted with 0, 1, or 2 substituents as described in the Definitionof Terms. Specific examples of heterocycles for the invention include,but are not limited to, morpholin-4-yl, thiomorpholin-4-yl, and4,5-dihydrothiazol-2-yl. Preferred heterocycles are dihydrothiazolyl,morpholinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, andtetrahydropyranyl.

Specific cycloalkyl groups for R₆ can include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

R₂ in a compound of formula (I) is absent when Z′ is N. R₂ also can beindependently selected from the group consisting of hydrogen, alkyl,alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy when Z′ is C.Preferred groups for R₂ are hydrogen, alkyl, and cycloalkyl.Alternatively, R₂ can be halogen, cyano, or L₂R₆, as defined for R₁. Incompounds wherein R₂ is a group of the formula L₂R₆, R₁ can be selectedfrom the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl,halogen, cyano, and thioalkoxy.

R₃ in a compound of formula (I) is absent when X′ is N. In addition, R₃can be independently selected from the group consisting of hydrogen,alkyl, alkoxy, cycloalkyl, halogen, cyano, and thioalkoxy when X′ is C.Preferred groups for R₃ are hydrogen, alkyl, and cycloalkyl.

R_(3a) in a compound of formula (I) is absent when Z is N. In addition,R_(3a) can be independently selected from the group consisting ofhydrogen, methyl, alkoxy, halogen, and cyano when Z is C. Preferredgroups for R_(3a) are hydrogen and methyl.

R_(3b) in a compound of formula (I) is absent when X is N. In addition,R_(3b) can be independently selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy when Xis C. Preferred groups for R_(3b) are hydrogen and hydroxy.

R₄ and R₅ in a compound of formula (I) are each independently selectedfrom the group consisting of alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NR_(A)R_(B))alkyl.Preferred compounds of formula (I), wherein R₄ and R₅ are independentlyselected are those wherein R₄ and R₅ are each independently selectedfrom methyl, ethyl, and propyl, particularly isopropyl.

R₄ and R₅ also can be taken together with the nitrogen atom to whicheach is attached form a non-aromatic ring of the formula:

wherein R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(x), R_(y), and m are asdescribed herein.

In one embodiment, R₄ and R₅ taken together with the nitrogen atom towhich each is attached form a 4- to 8-membered non-aromatic ringrepresented by formula (a).

R₇, R₈, R₉, and R₁₀ each can be independently selected from the groupconsisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl.Alternatively, each pair of R₇ and R₈ or R₉ and R₁₀ taken together canform a C₃-C₆ ring, including the carbon atom to which each is attached.The C₃-C₆ ring can include 0, 1, or 2 heteroatoms selected from O, N, orS to replace a carbon atom in the ring. Examples of C₃-C₆ rings caninclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, azetidinyl, pyrrolidinyl, oxirane, and the like.

R_(x) and R_(y) each can be independently selected from hydrogen,hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro. Also, oneof R_(x) and R_(y) can represent a bond when taken with R_(x) or R_(y)on an adjacent carbon atom, such that a double bond is representedbetween the adjacent carbon atoms.

The value represented by m can be selected from 1 to 5, inclusive.Preferred values for m are 2 and 3.

Compounds of formula (I) also are those wherein R₄ and R₅ are takentogether with the nitrogen atom to which each is attached to form anon-aromatic ring of formula (b), wherein R₇, R₈, R₉, and R₁₀ are aspreviously defined for a ring of formula (a); R₁₁, R₁₂, R₁₃, and R₁₄ areeach independently selected from the group consisting of hydrogen,hydroxy, hydroxyalkyl, alkyl, and fluoro; and Q is a bond or Q isselected from the group consisting of O, S, and NR₁₅, wherein R₁₅ isselected from the group consisting of hydrogen, alkyl, acyl, amido, andformyl. Preferably, R₇, R₈, R₉, and R₁₀ are each independently selectedfrom hydrogen, methyl, ethyl, fluoromethyl, and hydroxymethyl. R₁₁, R₁₂,R₁₃, and R₁₄ preferably each are hydrogen. Alternatively, it ispreferred that R₁₁ and R₁₂ are hydrogen, R₁₃ and R₁₄ are eachindependently selected from hydrogen or alkyl, and R₇, R₈, R₉, and R₁₀are as previously defined.

Compounds wherein R₄ and R₅ taken together with the nitrogen atom towhich each is attached to form a 4- to 8-membered non-aromatic ring offormula (a) can include, but are not limited to, those wherein the 4- to8-membered non-aromatic ring is selected from azetidinyl, azepanyl,azepinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, andtetrahydropyridinyl. The ring can be substituted with 0, 1, or 2substituents as previously described for heterocycle groups in theDefinition of Terms. Preferred substituents are selected from the groupconsisting of alkyl, halogen, hydroxyalkyl, fluoroalkyl, and—NR_(A)R_(B).

Groups for R₄ and R₅ also can be taken together with the nitrogen atomto which each is attached to form a 4- to 8-membered non-aromatic ringof formula (a) or formula (b), wherein the ring is substituted with atleast one substituent selected from hydroxy, alkyl, halogen,fluoroalkyl, or hydroxyalkyl.

More specific groups for R₄ and R₅ include, for example, those whereinR₄ and R₅ are taken together with the nitrogen atom to which each isattached to form a 4- to 8-membered non-aromatic ring selected frommorpholinyl and thiomorpholinyl, and unsubstituted or substitutedpyrrolidinyl, for example, methylpyrrolidinyl, ethylpyrrolidinyl,dimethylaminopyrrolidinyl, isopropylpyrrolidinyl, isobutylpyrrolidinyl,hydroxymethylpyrrolidinyl, and fluoromethylpyrrolidinyl. Pyrrolidinyl,and particularly methylpyrrolidinyl, for example 2-methylpyrrolidinyl,are preferred.

In one embodiment, groups for R₄ and R₅ are taken together with thenitrogen atom to which each is attached to form a non-aromatic ring offormula (a) or formula (b) and at least one of the substituents R₇, R₈,R₉, and R₁₀ is selected from hydroxyalkyl, fluoroalkyl, or alkyl. Inthis embodiment, at least one of R₇, R₈, R₉, and R₁₀ can be selectedfrom methyl, ethyl, fluoromethyl, or hydroxymethyl, and the like. Insuch embodiment, it is particularly preferred that one substituentrepresented by R₇, R₈, R₉, and R₁₀ is alkyl, and particularly methyl,and the other three substituents are hydrogen.

One specific embodiment relates to compounds having the formula (I)wherein R₄ and R₅ taken together with the nitrogen atom to which each isattached form a non-aromatic ring of formula (b) and Q is NR₁₅. In suchembodiment, R₁₅ preferably is selected from hydrogen, alkyl, amido, orformyl.

The moiety represented by L can be —[C(R₁₆)(R₁₇)]_(n)— or—[C(R₁₆)(R₁₇)]_(p)O—, wherein R₁₆ and R₁₇ are each independentlyselected from the group consisting of hydrogen, alkyl, alkoxy, andfluoro, and n is an integer selected from 1 to 6, inclusive, and p is aninteger selected from 2 to 6, inclusive. R₁₆ and R₁₇ preferably arehydrogen. The preferred value of n is 2 or 3. The preferred value for pis 2.

L₂ can be a bond or selected from —O—, —C(═O)—, —S—,—[C(R₁₈)(R₁₉)]_(q)—, —NH—, —N(alkyl)-, wherein R₁₈ and R₁₉ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkyl, alkoxy, and fluoro, and q is an integer selected from 1 to 4,inclusive. The alkyl group of —N(alkyl)- preferably contains from 1 to 6carbons. Compounds of the invention can have the formula (I) wherein L₂is —[C(R₁₈)(R₁₉)]_(q)—, R₁₈ and R₁₉ are hydrogen, and q is 1, 2, 3 or 4.The preferred value for q is 1.

Preferred compounds of formula (I) are those wherein R₁ is a group L₂R₆,wherein L₂ is a bond and R₆ is heteroaryl or heterocycle; R₂, R₃,R_(3a), and R_(3b) are hydrogen; L is —[C(R₁₆)(R₁₇)]_(n)—; n is 2; R₁₆and R₁₇ are hydrogen at each occurrence; R₄ and R₅ are taken together toform a methylpyrrolidinyl ring of formula (a), wherein one of R₇, R₈,R₉, and R₁₀ is methyl and the remaining three substituents are hydrogen;Y and Y′ are CH; X, X′, Z, and Z′ are C. A preferred heteroaryl group ispyridazinonyl and, more particularly, 2H-pyridazin-3-one-2-yl.

With respect to the ring system, 0, 1, or 2 atoms represented by X, X′,Y, Y′, Z, and Z′ can be nitrogen.

Compounds of the invention can have the formula (I) wherein Y and Y′ areCH; X, X′, Z, and Z′ are C; and R₂, R₃, R_(3a), and R_(3b) are hydrogen.

Alternatively, compounds of the invention have formula (I) wherein Y andY′ are CH; X, X′, and Z are C; R₃, R_(3a), and R_(3b) are hydrogen; Z′is N; and R₂ is absent.

Compounds of the invention also can have the formula (I) wherein Y andY′ are CH; X′, Z′, and Z are C; R₂, R₃, and R_(3a) are hydrogen; X is N;and R_(3b) is absent.

The invention also includes compounds having the formula (I) wherein Yand Y′ are CH; X, X′, and Z′ are C; R₂, R₃, and R_(3b) are hydrogen; Zis N; and R_(3a) is absent.

In another embodiment, compounds of the invention can have formula (I)wherein Y is CH; X, X′, Z, and Z′ are C; R₂, R₃, R_(3a), and R_(3b) arehydrogen; and Y′ is N.

In yet another embodiment, compounds of the invention have formula (I)wherein Y and Y′ are CH; X and Z′ are C; R₂ and R_(3b) are hydrogen; X′is N; Z is N; and R₃ and R_(3a) are absent.

Yet another embodiment relates to compounds of the invention having theformula (I) wherein X, X′, Z, and Z′ are C; R₂, R₃, R_(3a), and R_(3b)are hydrogen; Y is N; and Y′ is N.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y′ is CH; X, X′, and Z are C; R₃, R_(3a),and R_(3b) are hydrogen; Y is N; Z′ is N; and R₂ is absent.

Another embodiment relates to compounds of the invention having theformula (I) wherein Y′ is CH; X, Z, and Z′ are C; R₂, R_(3a), and R_(3b)are hydrogen; Y is N; X′ is N; and R₃ is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y′ is CH; X, X′, and Z′ are C; R₂, R₃,and R_(3b) are hydrogen; Y is N; Z is N; and R_(3a) is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, X′, and Z are C; R₃, R_(3a),and R_(3b) are hydrogen; Y′ is N; Z′ is N; and R₂ is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y and Y′ are CH; Z′ and Z are C; R₂ andR_(3a) are hydrogen; X′ is N; X is N; and R₃ and R_(3b) are absent.

Compounds of the invention also can have the formula (I) wherein Y′ isCH; X, X′, Z and Z′ are C; R₂, R₃, R_(3a), and R_(3b) are hydrogen; andY is N.

In yet another embodiment, compounds of the invention have formula (I)wherein Y and Y′ are CH; X′ and Z′ are C; R₂ and R₃ are hydrogen; X isN; Z is N; and R_(3a) and R_(3b) are absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, Z′, and Z are C; R₂, R_(3a),and R_(3b) are hydrogen; Y′ is N; X′ is N; and R₃ is absent.

When substituents represented by R₂, R₃, R_(3a), and R_(3b) are present,Z′, X′, Z, and X respectively, represent a carbon atom to allow for thesubstituents represented by R₂, R₃, R_(3a), and R_(3b). Specificexamples of compounds of the invention include, but are not limited to:

-   4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   (2R)-1-[2-(6-bromo-2-naphthyl)ethyl]-2-methylpyrrolidine;-   1-[3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)phenyl]ethanone;-   2-[3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)phenyl]-2-propanol;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthonitrile;-   4-(6-{[(2R)-2-methyl-1-pyrrolidinyl]methyl}-2-naphthyl)benzonitrile;-   3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine;-   3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine;-   (3-fluorophenyl)(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)methanol;-   3,5-dimethyl-4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)isoxazole;-   4-(6-{2-[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[(3R)-3-hydroxy-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-{6-[2-(2-isobutyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile;-   4-{6-[2-(2-isopropyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile;-   4-(6-{2-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-{6-[2-(diethylamino)ethyl]-2-naphthyl}benzonitrile;-   4-{6-[2-(dimethylamino)ethyl]-2-naphthyl}benzonitrile;-   4-(6-{2-[ethyl(isopropyl)amino]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[tert-butyl(methyl)amino]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[(2S)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[(2R)-2-methyl-1-piperidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-{6-[2-(2,5-dihydro-1H-pyrrol-1-yl)ethyl]-2-naphthyl}benzonitrile;-   4-(6-{2-[methyl(propyl)amino]ethyl}-2-naphthyl)benzonitrile;-   4-(6-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-2-naphthyl)benzonitrile;-   5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyrimidine;-   4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)morpholine;-   2-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)-1,3-thiazole;-   4-(6-{2-[(2S)-2-(fluoromethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   (3-fluorophenyl)(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)methanone;-   2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one;-   2-methoxy-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine;-   4-(6-{2-[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile;-   4-{6-[2-(2-methyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile;-   4-{6-[2-(1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile;-   4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)thiomorpholine;-   1-{2-[(6-bromo-2-naphthyl)oxy]ethyl}pyrrolidine;-   3-{6-[2-(1-pyrrolidinyl)ethoxy]-2-naphthyl}benzonitrile;-   3-{6-[2-(1-pyrrolidinyl)ethoxy]-2-naphthyl}pyridine;-   3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy}-2-naphthyl)benzonitrile;-   3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy}-2-naphthyl)pyridine;-   4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)benzonitrile;-   6-(4-fluorophenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)benzonitrile;-   1-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)phenyl]ethanone;-   6-(4-methoxyphenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-[4-(trifluoromethyl)phenyl]quinoline;-   2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-[4-(methylsulfonyl)phenyl]quinoline;-   6-(3,5-difluorophenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   (3-fluorophenyl)(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)methanone;-   2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-(3-pyridinyl)quinoline;-   4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile;-   3-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-pyridinyl)quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyridinyl)quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1,3-thiazol-2-yl)quinoline;-   2-(2,4-dimethyl-1,3-thiazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyrazinyl)quinoline;-   1-[6-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-pyridinyl]ethanone;-   4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrile;-   4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrile;-   7-(2,6-difluoro-3-pyridinyl)-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline;-   3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-(3-pyridinyl)isoquinoline;-   3-(benzyloxy)-2-methyl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   2-cyclopropyl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)benzonitrile;-   2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)nicotinonitrile;-   2-(3-methyl-2-pyrazinyl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   ethyl    5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-3-isoxazolecarboxylate;-   5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarbonitrile;-   ethyl    5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarboximidoate;-   2-(2,4-dimethyl-1,3-oxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;-   ethyl    3-methyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-4-isoxazolecarboxylate;-   4-(7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-3-isoquinolinyl)benzonitrile;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxaline;-   7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxaline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-phenylquinoxaline;-   7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-phenylquinoxaline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinazoline;-   6-methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   5-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine-2-carbonitrile;-   1-{6-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-one;-   5-{6-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-nicotinonitrile;-   4-methyl-1-{6-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-one;-   2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrazine;-   2-{6-[2-((2R)-2-methyl-2,5-dihydro-pyrrol-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   4-(6-{2-[(2-dimethylamino-ethyl)-methyl-amino]-ethyl}-naphthalen-2-yl)-benzonitrile;-   4-{6-[2-(4-methyl-piperazin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile;-   2-(2,5-dimethyl-furan-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-methylsulfanyl-phenyl)-quinoline;-   2-(6-methyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-3-yl-quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-pyrimidin-5-yl-quinoline;-   2-(2,6-dimethyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   1-[2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-pyridin-3-yl]-ethanone;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2H-pyrazol-3-yl)-quinoline;-   2-(3-bromo-isoxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   2-(6-chloro-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   2-(3,5-dimethyl-thiophen-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-2-yl-quinoline;-   2-furan-3-yl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   2-(4,5-dihydro-thiazol-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   1-[4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-phenyl]-ethanone;-   3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-2-trifluoromethyl-pyridin-4-ol;-   2-(3,5-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;-   6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1H-pyrazol-4-yl)-quinoline;-   2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-nicotinamide;-   2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-6-pyridin-4-yl-quinoline;-   6-(6-methoxy-pyridin-3-yl)-2-[2(R)-(2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(2,6-difluoro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(6-chloro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(2,6-dichloro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-pyrazin-2-yl-quinoline;-   2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-pyrimidin-5-yl-quinoline;-   6-(2,4-dimethoxy-pyrimidin-5-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   dimethyl-(4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-amine;-   1-(4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-ethanone;-   6-(4-chloro-phenyl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(2,6-dimethyl-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(5-methoxy-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   6-(3,5-dimethyl-isoxazol-4-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-benzoic    acid methyl ester;-   2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-(4-methylsulfanyl-phenyl)-quinoline;-   6-(6-fluoro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;-   5-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-nicotinonitrile;-   2,4-dimethoxy-5-{6-[2-((2R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine;-   2,6-difluoro-3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine;-   cyclopropyl-(4-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-phenyl)-methanone;-   3-methoxy-6-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazine;-   4-{6-[2-(2-methyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile;-   4-{6-[2-((2R)-2-ethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile;-   2-{6-[2-((2S)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-[6-((2R)-2-piperidin-1-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one;-   2-{6-[2-(tert-butyl-methyl-amino)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-[6-(2-diethylamino-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one;-   2-[6-(2-morpholin-4-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one;-   2-{6-[2-(ethyl-methyl-amino)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((2S)-2-fluoromethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((R)-2-ethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-[6-(2-azetidin-1-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one;-   2-{6-[2-((2S)-2-fluoromethyl-azetidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((2S)-2-hydroxymethyl-azetidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((2R,5R)-2,5-dimethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((2R,6S)-2,6-dimethyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((R)-3-hydroxy-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2-{6-[2-((R)-2-methyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one;-   2,6-dimethyl-3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine;-   5-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-thiazole;-   2-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine;-   3-chloro-6-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazine;-   5-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidin-2-ylamine;-   2-methyl-5-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine;-   3-bromo-7-(2-pyrrolidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-bromo-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine;-   3-bromo-7-(2-piperidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-(2,6-dimethyl-pyridin-3-yl)-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine;-   3-(2,4-dimethoxy-pyrimidin-5-yl)-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine;-   3-(2,6-dimethyl-pyridin-3-yl)-7-(2-pyrrolidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-(2,4-dimethoxy-pyrimidin-5-yl)-7-(2-pyrrolidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-(2,6-dimethyl-pyridin-3-yl)-7-(2-piperidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-(2,4-dimethoxy-pyrimidin-5-yl)-7-(2-piperidin-1-yl-ethyl)-[1,5]naphthyridine;-   3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-7-pyridin-4-yl-isoquinoline;-   7-(6-methoxy-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline;-   3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-7-pyrimidin-5-yl-isoquinoline;-   7-(6-fluoro-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline;-   5-{3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinolin-7-yl}-nicotinonitrile;-   7-(3-chloro-pyridin-4-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline;-   7-bromo-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-4-ol;-   4-{3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   7-bromo-4-chloro-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   4-{4-hydroxy-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-{4-isopropoxy-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-[3-(2-piperidin-1-yl-ethyl)-cinnolin-7-yl]-benzonitrile;-   4-[3-(2-pyrrolidin-1-yl-ethyl)-cinnolin-7-yl]-benzonitrile;-   4-{3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-{3-[2-((2R)-2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-[3-(2-morpholin-4-yl-ethyl)-cinnolin-7-yl]-benzonitrile;-   4-{3-[2-(4-methyl-piperidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   4-{3-[2-(ethyl-methyl-amino)-ethyl]-cinnolin-7-yl}-benzonitrile;-   7-(2,6-dimethyl-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   7-(2,4-dimethoxy-pyrimidin-5-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   7-(6-methoxy-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   3-{3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile;-   5-{3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-nicotinonitrile;-   7-(4-fluoro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   2-{3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-pyrrole-1-carboxylic    acid tert-butyl ester;-   (3-{3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-phenyl)-methanol;-   7-(3,5-difluoro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-7-thiophen-3-yl-cinnoline;-   7-(4-chloro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   7-(4-ethoxy-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline;-   3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-7-(1H-pyrrol-2-yl)-cinnoline;    and-   2-(1,5-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;    or a pharmaceutically acceptable salt thereof.

A preferred compound is2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one,which also can be named2-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)-3(2H)-pyridazinone.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: Ac for acetyl; atm for atmosphere(s);BINAP for 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc forbutyloxycarbonyl; Bu for butyl; DCM for dichloromethane; DMAP for4-(N,N-dimethylamino)pyridine; DMF for N,N-dimethylformamide; DMSO fordimethylsulfoxide; Et for ethyl; EtOH for ethanol; EtOAc for ethylacetate; HPLC for high pressure liquid chromatography; IPA for isopropylalcohol; IPAC or IPAc for isopropyl acetate; LDA for lithiumdiisopropylamide; NBS for N-bromosuccinimide; NIS for N-iodosuccinimide;Me for methyl; MeOH for methanol; Ms for methanesulfonyl; MTBE fortert-butyl methyl ether; Pd for palladium; tBu for tert-butyl; TEA fortriethylamine; TFA for trifluoroacetic acid; THF for tetrahydrofuran;and Ts for p-MePhS(O)₂—.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-24.

Compounds of formula (8) and (10), wherein X, X′, Y, Y′, Z, Z′, R₂, R₃,R₄, and R₅ are as defined in formula (I) and R₆ is aryl or heteroaryl,can be prepared as described in Scheme 1. Bromides of formula (1),purchased or prepared using methodology known to those of ordinary skillin the art, can be treated with lithium diisopropylamine and achloroformate such as, but not limited to, ethyl chloroformate toprovide esters of formula (2). Esters of formula (2) can be treated witha reducing agent such as, but not limited to, lithium borohydride toprovide alcohols of formula (3). Alcohols of formula (3) can be treatedwith a base such as, but not limited to, triethylamine and a sulfonatesuch as, but not limited to, methanesulfonyl chloride orp-toluensulfonyl chloride or triflic anhydride to provide sulfonates offormula (4). Sulfonates of formula (4) can be treated with an optionalbase such as, but not limited to, potassium carbonate or sodiumcarbonate and an amine of formula (5) with or without heat to provideamines of formula (6).

The Suzuki reaction can be used to produce compounds of formula (I),

wherein R₁ is an aryl, heteroaryl, heterocyclic, or cycloalkyl ring. Insuch a Suzuki reaction, compounds of formula (I) wherein R₁ is atriflate or halogen are reacted with boronic acids of formula (7), ametal catalyst such as, but not limited to, palladium diacetate orPd(PPh₃)₄, optionally with a Pd ligand added such as(dicyclohexylphosphinyl)biphenyl or trifurylphosphine, and a base suchas, but not limited to, aqueous 0.2 M K₃PO₄ to provide products offormula (I) wherein R₁ is an aryl, heteroaryl, heterocyclic orcycloalkyl ring. Boronic acid esters of formula (7a) can be used inplace of boronic acids. Boronic acids can be esterified to thecorresponding boronic acid esters with alcohols such as methanol or withdiols such as pinacol. Likewise, amines of formula (6) can be subjectedto the Suzuki reaction to provide amines of formula (8).

There are many aryl, heteroaryl, and heterocyclic boronic acids andboronic acid esters that are available commercially or that can beprepared as described in the scientific literature of synthetic organicchemistry. The preparation of boronic acid and boronic acid esterreagents suitable for incorporating into the synthetic methods forpreparing compounds of formula (I) are more specifically described inReference Example 2 herein.

Alternatively, using the Stille coupling, compounds of formula (8) maybe prepared from compounds of formula (6) by treatment with aryl,heteroaryl, and heterocyclic stannanes (Me₃SnR₆, Bu₃SnR₆), a palladiumsource such as tris(dibenzylidineacetone)dipalladium (CAS #52409-22-0)or palladium diacetate, and a ligand such as tri(2-furyl)phosphine (CAS#5518-52-5) or triphenyl arsine in a solvent, for example in DMF at25-150° C. While many organotin reagents for the Stille coupling arecommercially available or described in the literature, new organotinreagents can be prepared from arylhalides, aryltriflates,heteroarylhalides, heteroaryltriflates by reaction with distannanes like(Me₃Sn)₂ (hexamethyl distannane) in the presence of a palladium sourcelike Pd(Ph₃P)₄. Such methods are described, for instance, in Krische,et. al., Helvetica Chimica Acta 81(11):1909-1920 (1998), and inBenaglia, et al., Tetrahedron Letters 38:4737-4740 (1997). Thesereagents can be reacted with (6) to give (8) as described under Suzukiconditions, or for example under the conditions reported by Littke,Schwartz, and Fu, Journal of the American Chemical Society 124:6343-6348(2002).

Compounds of formula (8) wherein the R₆ group is a nitrogen-containingheteroaryl or heterocyclic ring linked to the bicyclic core groupthrough a nitrogen may be prepared by heating compounds of formula (6)with the H—R₆ (R₆=heteroaryl or heterocyclic group) with a base such as,but not limited to, sodium t-butoxide or cesium carbonate, in thepresence of a metal catalyst such as, but not limited to copper metal orCuI, palladium diacetate, and also optionally with a ligand such as, butnot limited to, BINAP, tri-tertbutylphosphine in solvents such asdioxane, toluene and pyridine. References that describe thesemethodologies may be found in the following references: J. Hartwig etal., Angew. Chem. Int. Ed. 37:2046-2067 (1998); J. P. Wolfe et al., Acc.Chem. Res., 13:805-818 (1998); M. Sugahara et al., Chem. Pharm. Bull.,45:719-721 (1997); J. P. Wolfe et al., J. Org. Chem., 65:1158-1174,(2000); F. Y. Kwong et al., Org. Lett., 4:581-584, (2002); A. Klapars etal., J. Amer. Chem. Soc., 123:7727-7729 (2001); B. H. Yang et al., J.Organomet. Chem., 576:125-146 (1999); and A. Kiyomori et al., Tet.Lett., 40:2657-2640 (1999). Additional references may also be found inHartwig, J. Org. Chem., 64(15):5575-5580 (1999), where compounds ofstructure (6) can be transformed to compounds of structure (8) or (11)by reaction with amines, anilines, amides with tris-tert-butyl phosphineand a palladium source such as Pd(OAc)₂. Compounds of structure (6) canbe transformed to heterocyclic or heteroaryl compounds of structure (8)where the R₆ moiety is, for instance, a N-pyridazinone by heating with3(2H)-pyridazinone (or an optionally functionalized heterocycle thatcontains an acidic NH group in the heterocycle, such as pyridin-2-one)with copper powder and base as described in WO 0024719, p. 127, Example62.

Compounds of formula (6) can also be treated with an organolithiumreagent such as, but not limited to, n-butyllithium, methyllithium, ortert-butyllithium and an amide of formula (9) to provide compounds offormula (10).

Compounds of formula (11), wherein L₂ is —NH— or —N(alkyl)- and R₆ is asdefined for a compound of formula (I) can be prepared by heatingcompounds of formula (6) with a compound of formula H₂N—R₆ orHN(alkyl)-R₆ with a base such as, but not limited to sodium t-butoxideor cesium carbonate in the presence of a metal catalyst such as, but notlimited to copper metal or CuI, palladium diacetate, and also optionallywith a ligand such as, but not limited to, BINAP, tri-tertbutylphosphinein solvents such as dioxane, toluene, pyridine. References that describethese methodologies may be found in the following references: J.Hartwig, et al., Angew. Chem. Int. Ed., 37:2046-2067 (1998); J. P. Wolfeet al., Acc. Chem. Res., 13:805-818 (1998); J. P. Wolfe et al., J. Org.Chem., 65:1158-1174 (2000); F. Y. Kwong et al., Org. Lett., 4:581-584,(2002); and B. H. Yang et al., J. Organomet. Chem., 576:125-146 (1999).

Compounds of formula (11), wherein L₂ is oxygen and R₆ is defined informula (I) can be prepared by heating compounds of formula (6) with acompound of formula HOR₆ using a base such as but not limited to sodiumhydride in a solvent such as toluene or N,N-dimethylformamide in thepresence of a metal containing catalyst such as CuI or palladiumdiacetate. References that describe these methodologies may be found inthe following references: J. Hartwig et al., Angew. Chem. Int. Ed.,37:2046-2067 (1998); J.-F. Marcoux et al., J. Am. Chem. Soc.,119:10539-10540 (1997); A. Aranyos et al., J. Amer. Chem. Soc.,121:4369-4378 (1999); M. Palucki et al., J. Amer. Chem. Soc.,119:3395-3396 (1997); and T. Yamamoto et al., Can. J. Chem., 61:86-91(1983). Additional methodologies useful for the synthesis of compoundsof formula (11), wherein the L₂ is oxygen and R₆ is defined in formula(I) can be found in the following references: A. Aranyos et al., J.Amer. Chem. Soc., 121:4369-4378 (1999); and E. Baston et al., Synth.Commun., 28:2725-2730 (1998).

Compounds of formula (11), wherein L₂ is sulfur and R₆ is as defined fora compound of formula (I) can be prepared by heating compounds offormula (6) with a compound of formula HSR₆ using a base with or withouta metal catalyst such as CuI or palladium diacetate in the presence of abase in a solvent such as dimethylformamide or toluene. References thatdescribe these methodologies may be found in the following references:G. Y. Li et al., J. Org. Chem., 66:8677-8681 (2001); G. Y. Li et al.,Angew. Chem. Int. Ed., 40:1513-1516 (2001); U. Schopfer et al.,Tetrahedron, 57:3069-3074 (2001); and C. Palomo et al., Tet. Lett.,41:1283-1286 (2000). Additional methodologies useful for the synthesisof compounds of formula (11), wherein the L₂ is oxygen and R₆ is definedin formula (1) can be found in the following reference A. Toshimitsu etal., Het. Chem., 12:392-397 (2001).

Compounds of formula (11), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q) and R₆, R₁₈and R₁₉ are as defined for a compound of formula (I) and q=1, can beprepared from compounds of formula (10). Compounds of formula (10) canbe manipulated by reactions well known to those skilled in the art oforganic chemistry such as the Grignard reaction, catalytichydrogenation, metal hydride reaction, alkylation of alcohols,fluorination with (diethylamino)sulfur trifluoride, fluorination with[bis(2-methoxyethyl)amino]sulfur trifluoride to provide compounds offormula (11), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q) and R₆, R₁₈ and R₁₉ aredefined in for a compound of formula (I) and q=1.

Compounds of formula (11), wherein L₂ is —[C(R₁₈)(R₁₉)]_(q) and R₆, R₁₈,R₁₉ and q are as defined for a compound of formula (I) can be preparedby cross-coupling reactions known to those skilled in the art. Examplesof these reactions are the Kumada, Suzuki, Heck, Stille,Suzuki-Miyaaura, Tamao-Kamuda and Sonogashira reaction. Suitablereagents, for example, alkyl Grignard reagents, boronic acids or ester,tin intermediates, alkenes and alkynes can be coupled with compounds offormulas (6) in the presence of a metal catalyst such as palladium,nickel, silver or indium, to prepare compounds of formula (11) whereinL₂ is a substituted or unsubstituted alkyl, alkenyl or alkynyl chain.Compounds of formula (11) wherein L₂ is an alkenyl or alkynyl chain canbe reduced to compounds of formula (11) wherein L₂ is an alkyl bymethods known to those skilled in the art such as catalytichydrogenation. References that describe these methodologies may be foundin the following references: G. A. Molander et al., Tetrahedron,58:1465-1470 (2002); W. Dohle et. al., Org. Lett., 3:2871-2873 (2001);G. Zou et al, Tet. Lett., 42:7213-7216 (2001); A. J. Suzuki, Organomet.Chem., 576:147-168 (1999); A. F. Littke, J. Amer. Chem. Soc.,122:4020-4028 (2000); N. Miyaura et al., Chem. Rev., 95:2457-2483(1995); H. Horie et al., J. Mater. Chem., 11:1063-1071 (2001); C. Dai etal., J. Amer. Chem. Soc., 123:2719-2724 (2001); F. Diederich et al.,Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH; Weinheim, 1998; A.Mohanakrishnan et al., Syn. Lett., 7:1097-1099 (1999); B. H. Lipshutz etal., Org. Lett., 3:1869-1872 (2001); B. H. Lipshutz et al., Tet. Lett.,40:197-200 (1999); and J. Tsuji, Palladium Reagents andCatalysts—Innovations in Organic Synthesis, John Wiley & Sons: New York,1995.

Alternatively, compounds of formula (8), wherein X, X′, Y, Y′, Z, Z′,R₂, R₃, R₄, and R₅ are as defined in formula (I) and R₆ is aryl orheteroaryl, can be prepared as described in Scheme 2. Esters of formula(13) can be treated with a reducing agent such as, but not limited to,lithium aluminum hydride to provide alcohols of formula (14). Alcoholsof formula (14) can be treated with thionyl chloride to providechlorides of formula (15). Chlorides of formula (15) can be treated withsodium cyanide or potassium cyanide to provide the nitrile which can betreated with aqueous acid to provide acids of formula (16). Acids offormula (16) can be treated with a reducing agent such as, but notlimited to, diborane or borane THF complex to provide alcohols offormula (17). Alcohols of formula (17) can be treated with ahydroxy-protecting reagent such as, but not limited to,tert-butyldimethylsilyl chloride. The protected compounds of formula(18) can be processed as described in Scheme 1 to provide compounds offormula (19). Compounds of formula (19) can be deprotected using methodsknown to those of ordinary skill in the art and then treated with asulfonyl chloride such as, but not limited to, methanesulfonyl chlorideor p-toluensulfonyl chloride to provide sulfonates of formula (20).Sulfonates of formula (20) can be treated with an amine of formula (5)to provide compounds of formula (8).

Compounds of formula (26), wherein X, X′, Y, Y′, Z, Z′, R₂, R₃, R₄, andR₅ are as defined in formula (I) and R₆ is aryl or heteroaryl, can beprepared as described in Scheme 3. Hydroxy compounds of formula (23),purchased or prepared using methods known to those of ordinary skill inthe art, can be treated with 1,2-dibromoethane to provide bromides offormula (24). Bromides of formula (24) can be treated with amines offormula (5) to provide compounds of formula (25). Compounds of formula(25) can be processed as described in Scheme 1 to provide compounds offormula (26).

Compounds of formula (34), wherein Y, Y′, Z′, R₂, R₄, and R₅ are asdefined in formula (I) and R₆ is aryl or heteroaryl, can be prepared asdescribed in Scheme 4. Indanones of formula (28) can be treated with abase such as, but not limited to, lithium diisopropylamide and ethylbromoacetate to provide esters of formula (29). Esters of formula (29)can be treated with tert-butylamineborane and then an aqueous basicsolution such as, but not limited to, sodium hydroxide in water toprovide hydroxyacids of formula (30). Hydroxyacids of formula (30) canbe treated with a strong acid such as, but not limited to, concentratedsulfuric acid with heat in a solvent such as methanol to provide estersof formula (31). Esters of formula (31) can be treated with a reducingagent such as, but not limited to, lithium aluminum hydride to providealcohols of formula (32). Alcohols of formula (32) can be treated withozone followed by dimethylsulfide and ammonium hydroxide to provideisoquinolines of formula (33). Isoquinolines of formula (33) can beprocessed as described in Schemes 1 and 2 to provide compounds offormula (34).

Compounds of formula (42), wherein R₂, R₃, R₄, R₅ and R₆ are as definedin formula (I) and L₂ is —[C(R₁₈)(R₁₉)]_(q)— or a bond can be preparedas described in Scheme 5. 1-(2-Bromoethyl)-4-nitrobenzene can be treatedwith amines of formula (5) to provide amines of formula (37). Amines offormula (37) can be treated with palladium on carbon under a hydrogenatmosphere to provide anilines which can then be treated with a nitrogenprotecting reagent such as, but not limited to, trimethylacetyl chlorideto provide protected anilines of formula (38). Protected anilines offormula (38) can be treated with an organolithium reagent such as, butnot limited to, n-butyllithium, sec-butyllithium, or tert-butyllithiumand N,N-dimethylformamide to provide aldehydes of formula (39). Theaniline of aldehydes of formula (39) can be deprotected using methodswell know to those skilled in the art such as, but not limited to,heating in aqueous hydrochloric acid to provide aldehydes of formula(40). Aldehydes of formula (40) can be treated with ketones of formula(41) and a base such as, but not limited to, potassium ethoxide toprovide compounds of formula (42).

Compounds of formula (44), wherein R₁, R₃, R₄, R₅ and R₆ are as definedin formula (I) and L₂ is —[C(R₁₈)(R₁₉)]_(q)— or a bond can be preparedas described in Scheme 5. Aldehydes of formula (40) can be treated withketones of formula (43) and a base such as, but not limited to,potassium ethoxide to provide compounds of formula (44).

Compounds of formula (41) and (43) can be purchased commercially orsynthesized from procedures which are known to those skilled in the art.

Compounds of formula (50), wherein R₄ and R₅ are as defined in formula(I) and R₆ is aryl or heteroaryl, can be prepared as described in Scheme6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared usingthe procedures described in Synthetic Comm., 17(14):1647-1653 (1987).Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with areducing agent, such as, but not limited to, lithium aluminum hydride orsodium borohydride, to provide(7-methoxy-2-methyl-3-quinolinyl)methanol.(7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with achlorinating reagent, such as, but not limited to, thionyl chloride toprovide 3-(chloromethyl)-7-methoxy-2-methylquinoline.3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodiumcyanide or potassium cyanide to provide(7-methoxy-2-methyl-3-quinolinyl)acetonitrile.(7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid,such as, but not limited to, glacial acetic acid and concentratedsulfuric acid, in water and 1,4-dioxane with heat to provide(7-methoxy-2-methyl-3-quinolinyl)acetic acid.(7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with areducing agent, such as, but not limited to, B₂H₆, borane-THF complex,or borane-pyridine complex, to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethanol.2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated withmethanesulfonyl chloride and a base, such as, but not limited to,triethylamine or diisopropylamine to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate.2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treatedwith an amine of formula (5) to provide amines of formula (47). Aminesof formula (47) can be treated with BBr₃ to provide hydroxy compounds offormula (48). Hydroxy compounds of formula (48) can be treated withtrifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chlorideto provide triflates of formula (49). Triflates of formula (49) can betreated with boronic acids of formula (7) as described in Scheme 1 toprovide compounds of formula (50).

1,5-Naphthyridines of formula (53), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl, can be prepared as describedin Scheme 7. 3,7-Dibromo-[1,5]naphthyridine, prepared as described by W.W. Paudler, J. Org. Chem., 33:1384 (1968), can be treated with(2-ethoxyvinyl)tributylstannane, a halide source, such as, but notlimited to, tetraethylammonium chloride, and a palladium source, suchas, but not limited to, dichlorobis(triphenylphosphine)palladium (II) ina solvent, such as, but not limited to, N,N-dimethylformamide with heat(about 50° C. to about 150° C.) to provide3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine.3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid,such as, but not limited to, formic acid at about 0° C. to about 60° C.in a solvent, such as, but not limited to, 1,2-dichloroethane to provide(7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively,3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, butnot limited to, tetrahydrofuran can be treated with an aqueous acid,such as, but not limited to, hydrochloric acid at about 0° C. to about60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde.(7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amineof formula (5) under reductive amination conditions, such as, but notlimited to, sodium triacetoxyborohydride and an acid, such as, but notlimited to, acetic acid in a solvent, such as, but not limited to,1,2-dichloroethane at about 0° C. to about 50° C. to provide amines offormula (52). Amines of formula (52) can be treated with boronic acidsof formula (7), a palladium source, such as, but not limited to,tris(dibenzylideneacetone)dipalladium (0), a ligand, such as, but notlimited to, tri(tert-butyl)phosphine, and a base, such as, but notlimited to, potassium fluoride in a solvent, such as, but not limitedto, tetrahydrofuran at about 20° C. to about 80° C. to provide1,5-naphthyridines of formula (53).

Cinnolines of formula (60), wherein R₄ and R₅ are as defined in formula(I) and R₆ is aryl or heteroaryl, can be prepared as described in Scheme8. Amines of formula (5) can be treated with 3-butynyl methanesulfonateat room temperature with stirring for about 1 hour and then heated atabout 50° C. for about 24 hours. The mixture is allowed to cool to roomtemperature, and filtered. The filtrate is diluted with acetonitrile toprovide a 0.1 M solution of alkynes of formula (55) for use insubsequent steps. 5-Bromo-2-iodophenylamine, prepared as described bySakamoto in Chem. Pharm. Bull., 35:1823 (1987), can be treated withalkynes of formula (55), a source of palladium (II), such as, but notlimited to, Pd(Ph₃P)₂Cl₂, CuI, and a base, such as, but not limited to,triethylamine in an organic solvent, such as, but not limited to, DMF atabout 50° C. to about 80° C. to provide alkynes of formula (56). Alkynesof formula (56) can be treated with aqueous acid, such as but notlimited to aqueous HCl in the presence of sodium nitrite at about 0° C.to about 100° C. to provide hydroxy cinnolines of formula (57). Hydroxycinnolines of formula (57) can be treated with boronic acids of formula(7) as described in Scheme 1 to provide hydroxy cinnolines of formula(58). Hydroxy cinnolines of formula (58) can be treated withN-phenylbis(trifluoromethanesulfonimide) and a base, such as, but notlimited to, diisopropylethylamine in an organic solvent, such as, butnot limited to, 1,2-dichloroethane at about 25° C. to about 40° C. toprovide triflates of formula (59). Triflates of formula (59) can betreated with a catalytic palladium source, such as, but not limited to,palladium (II) acetate and a hydrogen donor, such as, but not limitedto, formic acid at about 25° C. to about 50° C. to provide cinnolines offormula (60).

Cinnolines of formula (60), wherein R₄ and R₅ are as defined in formula(I) and R₆ is aryl or heteroaryl, also can be prepared as described inScheme 9. 7-Chloro-3-cinnolinol, prepared as described by H. E.Baumgarten, J. Het. Chem., 6:333 (1969), can be treated withtrifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydrideand a base, such as, but not limited to, triethylamine or pyridine in asolvent, such as, but not limited to, dichloromethane at about 0° C. orroom temperature to provide 7-chloro-3-cinnolinyltrifluoromethanesulfonate. 7-Chloro-3-cinnolinyltrifluoromethanesulfonate can be treated with(2-ethoxyvinyl)tributylstannane, a halide source, such as, but notlimited to, tetraethylammonium chloride, and a palladium source, suchas, but not limited to, dichlorobis(triphenylphosphine)palladium (II) ina solvent, such as, but not limited to, N,N-dimethylformamide at about50° C. to about 150° C. to provide 7-chloro-3-(2-ethoxyvinyl)cinnoline.7-Chloro-3-(2-ethoxyvinyl)cinnoline can be processed as described inScheme 7 to provide amines of formula (62). Amines of formula (62) canbe treated with boronic acids of formula (7), a palladium source, suchas, but not limited to, dichloro(di-tert-butylphosphinous acid)palladium(II) dimer) or tris(dibenzylideneacetone)dipalladium (0),tri(tert-butyl)phosphine, and a base, such as, but not limited to,cesium fluoride, in a solvent, such as, but not limited to, 1,4-dioxaneat about 30° C. to about 120° C. to provide cinnolines of formula (60).

Cinnolines of formula (67), wherein R₄ and R₅ are as defined in formula(I) and R₆ is aryl or heteroaryl, can be prepared as described in Scheme10. 7-Chloro-3-cinnolinyl trifluoromethanesulfonate, prepared asdescribed in Scheme 9, can be treated with boronic acids of formula (7),a palladium source, such as, but not limited to,tris(dibenzylideneacetone)dipalladium (0), tricyclohexylphosphine (ortriphenylphosphine or tri(tert-butyl)phosphine), and a base, such as,but not limited to, potassium fluoride, in a solvent, such as, but notlimited to, tetrahydrofuran at about 20° C. to about 80° C. to providechlorides of formula (64). Chlorides of formula (64) can be treated with2-(2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, prepared asdescribed by C. M. Vogels in Chem. Commun. (2000) 1, 51, a palladiumsource, such as, but not limited to,tris(dibenzylideneacetone)dipalladium (0), tri(tert-butyl)phosphine or,in place of both, dichloro(di-tert-butylphosphinous acid)palladium (II)dimer and a base such as cesium fluoride, in a solvent, such as, but notlimited to, 1,4-dioxane at about 30° C. to about 120° C. to provideethers of formula (65). Ethers of formula (65) can be processed asdescribed in Scheme 7 to provide cinnolines of formula (67).

Quinolines of formula (73), wherein R₄ and R₅ are as defined in formula(I) and R₆ is aryl or heteroaryl, can be prepared as described in Scheme11. 2-(3-Nitrophenyl)ethanol, CAS 100-27-6, can be treated withmethanesulfonyl chloride (or toluenesulfonyl chloride), and a base, suchas, but not limited to, triethylamine in a solvent, such as, but notlimited to, methylene chloride to provide 2-(3-nitrophenyl)ethylmethanesulfonate. 2-(3-Nitrophenyl)ethyl methanesulfonate can be treatedwith amines of formula (5) and a base, such as, but not limited to,potassium carbonate in a solvent, such as, but not limited to,acetonitrile to provide amines of formula (70). Amines of formula (70)can be treated with hydrogen with a palladium source, such as but notlimited to palladium on carbon in a solvent, such as, but not limitedto, methanol, ethanol, or ethyl acetate to provide anilines of formula(71). Anilines of formula (71) can be treated with2,2,3-tribromopropanal as described in S. W. Tinsley, J. Amer. Chem.Soc. 77:4175-4176 (1955), to provide quinolines of formula (72).Quinolines of formula (72) can be treated with boronic acids of formula(7) and treated as described in Scheme 1 to provide quinolines offormula (73).

Naphthyridines of formula (80), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl, can be prepared as describedin Scheme 12. 3-Bromo-1-(phenoxycarbonyl)pyridinium chloride can betreated with Grignard reagents of formula (75) as described in D. Cominset al., J. Het. Chem. 1239-1243 (1983) to provide compounds of formula(76). Compounds of formula (76) can be treated with a base, such as, butnot limited to, lithium diisopropylamide and N,N-dimethylformamide, asdescribed in Numata et al, Synthesis, 1999, 306-311, to providecompounds of formula (77). Compounds of formula (77) can be treated with3-butyn-1-ol, CuI, a base, such as, but not limited to, triethylamine,and palladium source, such as, but not limited to, Pd(PPh₃)₂Cl₂ in asolvent, such as but not limited to N,N-dimethylformamide to providealkynes of formula (78). Alkynes of formula (78) can be treated withammonia at about 80° C. in a solvent, such as, but not limited to,ethanol to provide naphthyridines of formula (79). Naphthyridines offormula (79) can be processed as described in Scheme 1 to providenaphthyridines of formula (80).

Naphthyridines of formula (86), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl, can be prepared as describedin Scheme 13. 6-Bromo-2-pyridinecarbaldehyde can be treated withN-iodosuccinimide in sulfuric acid and acetic acid to provide6-bromo-3-iodo-2-pyridinecarbaldehyde and6-bromo-5-iodo-2-pyridinecarbaldehyde.6-Bromo-3-iodo-2-pyridinecarbaldehyde can be treated withtert-butylamine in a solvent, such as, but not limited to, THF toprovide imine (84). Imine (84) can be treated with 3-butyn-1-ol, CuI, abase, such as, but not limited to, triethylamine or diisopropylamine,and a palladium source, such as, but not limited to, Pd(PPh₃)₂Cl₂ in asolvent, such as but not limited to N,N-dimethylformamide to providealcohols of formula (85). Alcohols of formula (85) can be processed asdescribed in Scheme 1 to provide naphthyridines of formula (86).

Naphthyridines of formula (91), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl, can be prepared as describedin Scheme 14. Imines of formula (84), prepared as described in Scheme13, can be treated with alkynes of formula (88), CuI, a base, such as,but not limited to, triethylamine or diisopropylamine, and a palladiumsource, such as, but not limited to, Pd(PPh₃)₂Cl₂ in a solvent, such asbut not limited to N,N-dimethylformamide to provide naphthyridines offormula (89). Naphthyridines of formula (89) can be treated with analkyllithium reagent, such as, but not limited to, methyllithium,n-butyllithium, sec-butyllithium, or t-butyllithium, and ethylene oxidein a solvent, such as, but not limited to, THF or diethyl ether toprovide alcohols of formula (90). Alcohols of formula (90) can betreated as described in Scheme 1 to provide naphthyridines of formula(91).

Isoquinolines of formula (95), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl, can be prepared as describedin Scheme 15. Methyl 2-iodobenzoate can be treated withN-bromosuccinimide in acetic acid and sufuric acid to provide methyl5-bromo-2-iodobenzoate. Methyl 5-bromo-2-iodobenzoate can be treatedwith a reducing agent, such as, but not limited to, sodium borohydrideor lithium aluminum hydride in a solvent, such as, but not limited to,THF, ethanol, or a mixture thereof, to provide(5-bromo-2-iodophenyl)methanol. (5-Bromo-2-iodophenyl)methanol can betreated with an oxidizing agent, such as, but not limited to, pyridiniumchlorochromate, pyridinium dichromate, MnO₂, a peracid such asmeta-chloroperoxybenzoic acid, or Swern conditions (DMSO/Cl(CO)₂Cl/TEA)to provide 5-bromo-2-iodobenzaldehyde. 5-Bromo-2-iodobenzaldehyde can betreated with tert-butylamine in a solvent, such as, but not limited to,THF to provide N-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treatedwith alkynes of formula (88), CuI, a base, such as, but not limited to,triethylamine or diisopropylamine, and a palladium source, such as, butnot limited to, Pd(PPh₃)₂Cl₂ in a solvent, such as but not limited toN,N-dimethylformamide to provide isoquinolines of formula (93).Isoquinolines of formula (93) can be treated with an alkyllithiumreagent, such as, but not limited to, methyllithium, n-butyllithium,sec-butyllithium, or t-butyllithium, and ethylene oxide in a solvent,such as, but not limited to, THF or diethyl ether to provide alcohols offormula (94). Alcohols of formula (94) can be treated as described inScheme 1 to provide isoquinolines of formula (95).

Isoquinolines of formula (34a) are a subgenus of compounds (34), whereinX, Y′, and Z′ are all carbon atoms, for instance CH, and R₄ and R₅ areas defined in formula (I) and R₆ is aryl or heteroaryl, and thecompounds of the subgenus (34a) can be prepared as described in Scheme16. Methyl 2-iodobenzoate can be treated with N-bromosuccinimide inacetic acid and sulfuric acid to provide methyl 5-bromo-2-iodobenzoate.Methyl 5-bromo-2-iodobenzoate can be treated with a reducing agent, suchas, but not limited to, sodium borohydride or lithium aluminum hydridein a solvent, such as, but not limited to, THF, ethanol, or a mixturethereof, to provide (5-bromo-2-iodophenyl)methanol.(5-Bromo-2-iodophenyl)methanol can be treated with an oxidizing agent,such as, but not limited to, pyridinium chlorochromate, pyridiniumdichromate, MnO₂, a peracid such as meta-chloroperoxybenzoic acid, orSwern conditions (DMSO/Cl(CO)₂Cl/TEA) to provide5-bromo-2-iodobenzaldehyde. 5-Bromo-2-iodobenzaldehyde can be treatedwith tert-butylamine in a solvent, such as, but not limited to, THF toprovide N-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treatedwith the alkyne but-3-yn-1-ol, CuI, a base, such as, but not limited to,triethylamine or diisopropylamine, and a palladium source, such as, butnot limited to, Pd(PPh₃)₂Cl₂ in a solvent, such as, but not limited to,N,N-dimethylformamide to provide an isoquinoline. The2-hydroxyethylisoquinoline can be treated as described in Scheme 1 toprovide isoquinolines of formula (34a).

Quinoxalines of formula (105), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl, heteroaryl, heterocycle, or cycloalkyl, canbe prepared as described in Scheme 17. Amines of formula (37), preparedas described in Scheme 5, can be treated with palladium on carbon undera hydrogen atmosphere to provide anilines that can then be treated withacetic anhydride in a solvent such as a mixture of sulfuric acid andwater to provide acetamides of formula (100). Acetamides of formula(100) can be nitrated using conditions well known to those skilled inthe art such as, but not limited to, nitric acid in sulfuric acid in thepresence of acetic anhydride to provide acetamides of formula (101).Acetamides of formula (101) can be converted to Boc protectednitroanilines using a procedure described in Grehen, L, et. al, ActaChem. Scand. Ser. B. 41, 1, 18-23, in which the acetamide is reactedwith di-tert-butyldicarbonate in the presence of 4-dimethylaminopyridinefollowed by treatment with 2-diethylaminodiethylamine to provide a Bocprotected nitroaniline which can be treated with palladium on carbonunder a hydrogen atmosphere to provide anilines of formula (102).

Anilines of formula (102) can be reacted with an acetyl bromide offormula (103) to provide amines of formula (104). Amines of formula(104) can be treated with an acid such as trifluoroacetic acid withheating to provide quinoxalines of formula (105). Treatment of amines offormula (104) may result in the formation of dihydroquinoxalines offormula (106). Dihydroquinoxalines of formula (106) may be oxidized withan oxidant such as silver nitrate to provide quinoxalines of formula(105).

An alternate route to quinoxalines of formula (105), wherein R₄ and R₅are as defined in formula (I) and R₆ is aryl or heteroaryl, is describedin Scheme 18. Anilines of formula (102), prepared as described in Scheme17, can be reacted with a bromoacetate to provide anilines of formula(110). Anilines of formula (110) can be treated with an acid such as,but not limited to, trifluoroacetic acid with heating to providedihydroquinoxalinones of formula (111). Dihydroquinoxalinones of formula(111) can be oxidized using an oxidizing agent such as, but not limitedto, silver nitrate to provide quinoxalinones of formula (112).Quinoxalinones of formula (112) can be treated with triflic anhydride inthe presence of a base such as 2,6-lutidine in a solvent such asdichloromethane to provide triflates of formula (113). Triflates offormula (113) can be treated with boronic acids of formula (7) asdescribed in Scheme 1 to provide quinoxalines of formula (105).

Quinazolines of formula (123), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl, heteroaryl, heterocycle, or cycloalkyl, canbe prepared as described in Scheme 19. Anilines of formula (40),prepared as described in Scheme 5, can be treated with acid chlorides offormula (121) in the presence of a base such as pyridine in a solventsuch as dichloromethane to provide amides of formula (122). Amides offormula (122) can be treated with a source of ammonia, such as aqueousammonium hydroxide, and heated to provide quinazolines of formula (123).

Quinazolines of formula (123), wherein R₄ and R₅ are as defined informula (I) and R₆ is aryl or heteroaryl can also be prepared asdescribed in Scheme 20.

Anilines of formula (40), prepared as described in Scheme 5, can betreated with urea and heated as described in Troeger, et. al. Prakt.Chem. 117, 1927, 181, to provide quinazolinones of formula (130).Quinazolinones of formula (130) can be treated with triflic anhydride inthe presence of a base such as 2,6-lutidine in a solvent such asdichloromethane to provide triflates of general structure (131).Triflates of formula (131) can be treated with boronic acids of generalstructure (7) as described in Scheme 1 to provide quinoxalines offormula (123).

Compounds of formula (144) and (145), wherein Y, Y′, Z′, R₂, R₄, and R₅are as defined in formula (I) and R₆ is aryl or heteroaryl, can beprepared as described in Scheme 21. Nitrobenzenes of formula (138) canbe treated with a reducing agent such as, but not limited to, platinumon carbon under a hydrogen atmosphere to provide diaminobenzenes offormula (139). Diaminobenzenes of formula (139) can be treated with2-oxopropanal to provide a mixture of bromides of formula (140) and(141). Bromides of formula (140) and (141) can be treated withformaldehyde and amines of formula (5) to provide a mixture ofaminobromides of formula (142) and (143). Aminobromides of formula (142)and (143) can be processed as described in Scheme 1 to provide compoundsof formula (144) and (145).

Compounds of formula (154), wherein Y, Y′, Z′, R₂, R₄, and R₅ are asdefined in formula (I) and R₆ is aryl or heteroaryl, can be prepared asdescribed in Scheme 22. Compounds of formula (147), purchased orprepared using known methods in the art, can be treated with NaNO₂ andacid, such as, but not limited to, concentrated sulfuric acid followedby treatment with KI to provide iodo compounds of formula (148). Iodocompounds of formula (148) can be treated with SnCl₂ and an acid suchas, but not limited, concentrated HCl to provide compounds of formula(149). Compounds of formula (149) can be treated with but-3-yn-1-ol,copper (I) iodide, base such as, but not limited to triethylamine, and ametal catalyst such as but not limited to PdCl₂(PPh₃)₂ to providealkynes of formula (150). Alkynes of formula (150) can be treated withNaNO₂ and an acid such as, but not limited to, 6M HCl to providecompounds of formula (151).

Compounds of formula (151) can be treated with POCl₃ to providechlorides of formula (152). Chlorides of formula (152) can be treatedwith boronic acids of formula (7) as described in Scheme 1 to providecompounds of formula (153). Compounds of formula (153) can be treatedwith amines of formula (5) to provide compounds of formula (154).

Compounds of formula (159-161), wherein Y, Y′, Z′, R₂, R₄, and R₅ are asdefined in formula (I) and R₆ is aryl or heteroaryl, can be prepared asdescribed in Scheme 23. Compounds of formula (149), can be treated withamines of formula (55), copper (I) iodide, a base such as, but notlimited to triethylamine, and a metal catalyst such as, but not limitedto, PdCl₂(PPh₃)₂ to provide alkynes of formula (157). Alkynes of formula(157) can be treated with NaNO₂ and an acid such as, but not limited to,6 M HCl to provide compounds of formula (158). Compounds of formula(158) can be treated with boronic acids of formula (7) as described inScheme 1 to provide compounds of formula (159). Compounds of formula(159) can be treated with an alkyl halide such as, but not limited to,iodomethane or iodoethane and a base such as, but not limited to,triethylamine to provide compounds of formula (160). Compounds offormula (159) can be treated with phosphorus oxychloride to providechlorides of formula (161), phosphorus oxybromide may also be used togenerate the corresponding bromides.

An alternative method for preparing compounds of formula (160-161) andmethods for preparation of compounds of formula (167-169), wherein Y,Y′, Z′, R₂, R₄, and R₅ are as defined in formula (I) and R₆ is aryl orheteroaryl, is described in Scheme 24. Compounds of general formula(151), can be treated with a reagent for protecting a hydroxy groupknown to those of skill in the art such as, but not limited to,tert-butyldimethylsilyl chloride or benzyl bromide, and a base such as,but not limited to, sodium bicarbonate or imidazole to provide compoundsof formula (163) wherein PG is the hydroxy protecting group. Compoundsof formula (163) can be treated with methanesulfonyl chloride (ortoluenesulfonyl chloride) and a base such as, but not limited to,diisopropylamine or triethylamine to provide sulfonates of formula(164). Sulfonates of formula (164) can be treated with amines of formula(5) to provide compounds of formula (165). Compounds of formula (165)can be treated with boronic acids of formula (7) as described in Scheme1 to provide compounds of formula (166). The hydroxy protecting group ofcompounds of formula (166) can be removed using methods known to thosein the art such as, but not limited to, treatment with fluoride ion,acid, or hydrogenation in the presence of a metal catalyst (H₂ and Pd/C)followed by treatment with phosphorus oxychloride to provide chloridesof formula (161), phosphorus oxybromide may also be used to generate thecorresponding bromides. Chlorides of formula (161) can be treated withnucleophiles such as, but not limited to, alkoxides, alkyl mercaptans,alkyl grignards, or sodium cyanide to provide compounds of formula(167-169).

The invention also relates to preparing a compound of formula (I)

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein R₁ is L₂R₆ wherein L₂ is a bond and R₆ is3(2H)-pyridazinon-2-yl; R₂, R₃, R_(3a), and R_(3b) are hydrogen; L is—[C(R₁₆)(R₁₇)_(n)]—; n is 2; R₁₆ and R₁₇ at each occurrence arehydrogen; R₄ and R₅ are taken together to form a methylpyrrolidinyl ringof formula (a), wherein one of R₇, R₈, R₉, and R₁₀ is methyl and theremaining three substituents are hydrogen; Y and Y′ are CH; and X, X′,Z, and Z′ are C. The process comprises the steps of:

(a) providing a compound (II):

(b) reducing the compound (II) with BH₃-THF to provide a compound (III):

(c) treating the compound of formula (III) with 3(2H)-pyridazinone,copper powder, and base to provide a compound (IV):

(d) activating the hydroxy group of compound (IV); and reacting theresulting compound with methylpyrrolidine to provide a compound offormula (I).

Compound (II), 6-bromo-naphthalen-2-yl-acetic acid [CAS 3271-06-5] canbe prepared by various known methods, for example, Jones et al., J.Amer. Chem. Soc., 70:2843-2848 (1948). Compound (II) can be reduced bytreatment with borane-THF, preferably using from about three to fourequivalents while maintaining the reaction below 0° C. Compound (III)can be reacted with 3(2H)-pyridazinone by the method described in WO0024719, Example 62, using about one equivalent of copper powder andabout three equivalents of base. The preferred base is K₂CO₃. Compound(IV) can be activated by treatment with methanesulfonyl chloride ortoluensulfonyl chloride, preferably in the presence of a base, forexample triethylamine. The resulting compound can be reacted with anamine, for example methylpyrrolidine and, more particularly,2-methylpyrrolidine, to provide a compound within the scope of formula(I).

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric,gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic,malic, phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, refer to carboxylate salts, aminoacid addition salts, zwitterions, esters and amides of compounds offormula (I) which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Preferred salts of thecompounds of the invention are the tartrate and hydrochloride salts.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyliodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aryl halide. In thecase of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also may beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention may be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe effects of histamine-3 receptors. In particular, the compounds andcompositions of the invention can be used for treating and preventingdisorders modulated by the histamine-3 receptors. Typically, suchdisorders can be ameliorated by selectively modulating the histamine-3receptors in a mammal, preferably by administering a compound orcomposition of the invention, either alone or in combination withanother active agent as part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for the histamine-3receptors. As histamine-3 receptor ligands, the compounds of theinvention may be useful for the treatment and prevention of diseases orconditions such as acute myocardial infarction, Alzheimer's disease,asthma, attention-deficit hyperactivity disorder, bipolar disorder,cognitive dysfunction, cognitive deficits in psychiatric disorders,deficits of memory, deficits of learning, dementia, cutaneous carcinoma,drug abuse, diabetes, type II diabetes, depression, epilepsy,gastrointestinal disorders, inflammation, insulin resistance syndrome,jet lag, medullary thyroid carcinoma, melanoma, Meniere's disease,metabolic syndrome, mild cognitive impairment, migraine, mood andattention alteration, motion sickness, narcolepsy, neurogenicinflammation, obesity, obsessive compulsive disorder, pain, Parkinson'sdisease, polycystic ovary syndrome, schizophrenia, cognitive deficits ofschizophrenia, seizures, septic shock, Syndrome X, Tourette's syndrome,vertigo, and sleep disorders.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat septic shock andcardiovascular disorders, in particular, acute myocardial infarction maybe demonstrated by Imamura et al., Circ. Res., 78:475-481 (1996);Imamura et. al., Circ. Res., 78:863-869 (1996); R. Levi and N. C. E.Smith, “Histamine H₃-receptors: A new frontier in myocardial ischemia”,J. Pharm. Exp. Ther., 292:825-830 (2000); and Hatta, E., K. Yasuda andR. Levi, “Activation of histamine H₃ receptors inhibits carrier-mediatednorepinephrine release in a human model of protracted myocradialischemia”, J. Pharm. Exp. Ther., 283:494-500 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,in particular, narcolepsy may be demonstrated by Lin et al., Brain Res.,523:325-330 (1990); Monti, et al., Neuropsychopharmacology 15:31-35(1996); Sakai, et al., Life Sci., 48:2397-2404 (1991);Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol., 67:75-78(1989); P. Panula, et al., Neuroscience 44:465-481 (1998); Wada, et al.,Trends in Neuroscience 14:415 (1991); and Monti, et al., Eur. J.Pharmacol. 205:283 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cognition andmemory process disorders may be demonstrated by Mazurkiewicz-Kwileckiand Nsonwah, Can. J. Physiol. Pharmacol., 67:75-78 (1989); P. Panula, etal., Neuroscience, 82:993-997 (1997); Haas, et al., Behay. Brain Res.,66:41-44 (1995); De Almeida and Izquierdo, Arch. Int. Pharmacodyn.,283:193-198 (1986); Kamei et al., Psychopharmacology, 102:312-318(1990); Kamei and Sakata, Jpn. J. Pharmacol., 57:437-482 (1991);Schwartz et al., Psychopharmacology, The fourth Generation of Progress.Bloom and Kupfer (eds). Raven Press, New York, (1995) 397; and Wada, etal., Trends in Neurosci., 14:415 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat attention-deficithyperactivity disorder

(ADHD) may be demonstrated by Shaywitz et al., Psychopharmacology,82:73-77 (1984); Dumery and Blozovski, Exp. Brain Res., 67:61-69 (1987);Tedford et al., J. Pharmacol. Exp. Ther., 275:598-604 (1995); Tedford etal., Soc. Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behay. BrainRes., 131:151-161 (2002).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat seizures, inparticular, epilepsy may be demonstrated by Yokoyama, et al., Eur. J.Pharmacol., 234:129 (1993); Yokoyama and linuma, CNS Drugs 5:321 (1996);Onodera et al., Prog. Neurobiol., 42:685 (1994); R. Leurs, R. C.Vollinga and H. Timmerman, “The medicinal chemistry and therapeuticpotential of ligands of the histamine H₃ receptor”, Progress in DrugResearch 45:170-165, (1995); Leurs and Timmerman, Prog. Drug Res.,39:127 (1992); The Histamine H₃ Receptor, Leurs and Timmerman (eds),Elsevier Science, Amsterdam, The Netherlands (1998); H. Yokoyama and K.Iinuma, “Histamine and Seizures: Implications for the treatment ofepilepsy”, CNS Drugs, 5(5):321-330 (1995); and K. Hurukami, H. Yokoyama,K. Onodera, K. Iinuma and T. Watanabe, “AQ-0145, A newly developedhistamine H₃ antagonist, decreased seizure susceptibility ofelectrically induced convulsions in mice”, Meth. Find. Exp. Clin.Pharmacol., 17(C):70-73 (1995).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat motion sickness,Alzheimer's disease, and Parkinson's disease may be demonstrated byOnodera, et al., Prog. Neurobiol., 42:685 (1994); Leurs and Timmerman,Prog. Drug Res., 39:127 (1992); and The Histamine H₃ Receptor, Leurs andTimmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat narcolepsy,schizophrenia, depression, and dementia may be demonstrated by R. Leurs,R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor”, Progressin Drug Research 45:170-165 (1995); The Histamine H₃ Receptor, Leurs andTimmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998);and Perez-Garcia C, et. al., and Psychopharmacology (Berl) 142(2):215-20(February, 1999).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,cognitive dysfunction, mood and attention alteration, vertigo and motionsickness, and treatment of cognitive deficits in psychiatric disordersmay be demonstrated by Schwartz, Physiol. Review 71:1-51 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat mild cognitiveimpairment, deficits of memory, deficits of learning and dementia may bedemonstrated by C. E. Tedford, in “The Histamine H₃ Receptor: a targetfor new drugs”, the Pharmacochemistry Library, vol. 30 (1998) edited byR. Leurs and H. Timmerman, Elsevier (N.Y.). p. 269 and references alsocontained therein.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat obesity may bedemonstrated by Leurs, et al., Trends in Pharm. Sci., 19:177-183 (1998);E. Itoh, M. Fujimiay, and A. Inui, “Thioperamide, A histamine H₃receptor antagonist, powerfully suppresses peptide YY-induced foodintake in rats,” Biol. Psych., 45(4):475-481 (1999); S. I. Yates, etal., “Effects of a novel histamine H₃ receptor antagonist, GT-2394, onfood intake and weight gain in Sprague-Dawley rats,” Abstracts, Societyfor Neuroscience, 102.10:219 (November, 2000); and C. Bjenning, et al.,“Peripherally administered ciproxifan elevates hypothalamic histaminelevels and potently reduces food intake in the Sprague Dawley rat,”Abstracts, International Sendai Histamine Symposium, Sendai, Japan, #P39(November, 2000).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat inflammation andpain may be demonstrated by Phillips, et al., Annual Reports inMedicinal Chemistry 33:31-40 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat migraine may bedemonstrated by R. Leurs, R. C. Vollinga and H. Timmerman, “Themedicinal chemistry and therapeutic potential of ligands of thehistamine H₃ receptor,” Progress in Drug Research 45:170-165 (1995);Matsubara, et al., Eur. J. Pharmacol., 224:145 (1992); and Rouleau, etal., J. Pharmacol. Exp. Ther., 281:1085 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cancer, inparticular, melanoma, cutaneous carcinoma and medullary thyroidcarcinoma may be demonstrated by Polish Med. Sci. Mon., 4(5):747 (1998);Adam Szelag, “Role of histamine H₃-receptors in the proliferation ofneoplastic cells in vitro,” Med. Sci. Monit., 4(5):747-755 (1998); andC. H. Fitzsimons, et al., “Histamine receptors signalling in epidermaltumor cell lines with H-ras gene alterations,” Inflammation Res., 47(Suppl 1):550-551 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat vestibulardysfunctions, in particular, Meniere's disease may be demonstrated by R.Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor,” Progressin Drug Research 45:170-165 (1995), and Pan, et al., Methods andFindings in Experimental and Chemical Pharmacology 21:771-777 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat asthma may bedemonstrated by A. Delaunois A., et al., “Modulation of acetylcholine,capsaicin and substance P effects by histamine H₃ receptors in isolatedperfused rabbit lungs,” European Journal of Pharmacology277(2-3):243-250 (1995); and Dimitriadou, et al., “Functionalrelationship between mast cells and C-sensitive nerve fibres evidencedby histamine H₃-receptor modulation in rat lung and spleen,” ClinicalScience 87(2):151-163 (1994).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat allergic rhinitismay be demonstrated by McLeod, et al., Progress in Resp. Research 31:133(2001).

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting the memory or cognition,for example Alzheimer's disease, attention-deficit hyperactivitydisorder, schizophrenia, or the cognitive deficits of schizophrenia.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.003 to about 30mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.01 to about 0.1 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

REFERENCE EXAMPLES Reference Example 1 Preparation of(2R)-2-methylpyrrolidine and (2S)-2-methylpyrrolidine

(2R)-2-Methylpyrrolidine tartrate was prepared via resolution of2-methylpyrrolidine with D-tartaric acid using procedures described byWilliam Gaffield, et al. in Tetrahedron, 37:1861-1869 (1981) or,alternatively, prepared from L-prolinol by methods described by Karrerand Ehrhardt in Helv. Chim. Acta, 34: 2202, 2208 (1951).(2R)-2-methylpyrrolidine hydrobromide also is a suitable source of(2R)-2-methylpyrrolidine, and was prepared using the procedure describedby Nijhuis, Walter H. N., et al., J. Org. Chem., 54(1): 209-216, 214(1989). Other procedures describing the synthesis of(2R)-2-methylpyrrolidine and salts thereof can be found in Andres, JoseM., et al. Eur. J. Org. Chem., 9:1719-1726 (2000); and Elworthy, ToddR.; Meyers, A. I., Tetrahedron, 50(20): 6089-6096 (1994).

(2S)-2-Methylpyrrolidine can be substituted for (2R)-2-methylpyrrolidinein the experimental procedures provided herein. The(2S)-2-methylpyrrolidine can be prepared by procedures described in Kim,Mahn-Joo, et al., Bioorg. Med. Chem. Lett. 6(1):71-76 (1996).

Reference Example 2 Preparation of Boronic Acid and Ester Reagents

There are many aryl, heteroaryl, and heterocyclic boronic acids andboronic acid esters that are available commercially or that can beprepared as described in the scientific literature of synthetic organicchemistry. Non-exhaustive examples of boronic acid and boronic acidester reagents for the synthesis of compounds of formula (I) areprovided in Table 1, below, and the following description.

TABLE 1 Examples of Boronic Acid and Boronic Acid Ester Reagents BoronicAcid or Commercial Source, Chemical Abstracts Boronic Acid Ester Numberor Literature Reference 2-pyrimidinone-5- Matrix Scientific, Columbia,SC, USA boronic acid 1H-pyrimidine-2,4- Specs, Fleminglaan, theNetherlands dione-5-boranic acid pyridine-3-boronic acid 1692-25-7,Frontier Scientific, Inc., Logan, UT, USA 2,4-dimethoxypyrimidine-89641-18-9, Frontier Scientific, Inc., 5-boronic acid Logan, UT, USA2-methoxy-5-pyridine Digital Specialty Chemicals, Dublin, NH boronicacid pyrimidine-5-boronic acid S. Gronowitz, et al., “On the synthesisof various thienyl- and selenienylpyrimidines,” Chem. Scr. 26(2):305-309 (1986). pyrimidine-5-boronic acid, Umemoto, et al., Angew. Chem.Int. Ed. pinacol ester 40(14): 2620-2622 (2001).

Boronic acid esters of formula (7a):(R_(e)O)(R_(f)O)B—R₆  (7a)may serve as synthetic replacements for boronic acids of formula (7) inthe Schemes. The substituents represented by R_(e) and R_(f) incompounds of formula (7a) may be alkyl, or alternatively R_(e) and R_(f)can be taken together to form a ring, which may itself be substitutedwith alkyl or aryl groups. Examples of suitable compounds of formula(7a) include, but are not limited to (CH₃O)₂BPh and(4-cyanomethylphenyl)boronic acid, pinacol ester (CombiBlocks Inc., SanDiego)). Boronic acids of formula (7) and boronic acid esters of formula(7a) are commercially available or can be prepared by methods well knownto those skilled in the art of synthetic organic chemistry. Forinstance, Takagi et al. (Tetrahedron Letters, 43:5649-5651 (2002))prepared heteroaryl pinacolborane esters of formula (7a) usingheteroaromatic compounds and reaction with bis(pinacolborane) in thepresence of an iridium catalysis ofIrCl[COD]2-(4,4′-di-t-butyl-2,2′-bipyridine in octane. Other methodshave been described wherein aryl halides and heteroaryl halides aretransmetallated with alkyl lithiums or Grignard reagents, then treatedwith trialkylborate esters, then treated with acid to produce compoundsof formulae (7) and (7a) (B. T. O'Neill, et al., Organic Letters, 2:4201(2000); M. D. Sindkhedkar, et al., Tetrahedron, 57:2991 (2001); W. C.Black, et al., Journal of Medicinal Chemistry, 42:1274 (1999);Letsinger; Dandegaonker, J. Amer. Chem. Soc., 81:498-501 (1959);Carroll, F. Ivy, et al. J. Med. Chem., 2229-2237 (2001). Another methodis the Miyaura reaction described in Ishiyama, Tatsuo; Ishida, Kousaku,Miyaura, Norio, Tetrahedron, 9813-9816 (2001) in which aryl andheteroaryl halides are reacted with bis(pinacolborane), KOAc, and Pd₂dba₃ and tris-cyclohexylphosphine or PdCl₂dppf (Ishiyama, et al.Tetrahedron, 9813-9816 (2001)). Another method for preparation ofcompounds of formula (7a) is the reaction described in O. Baudoin, etal., J. Org. Chem., 65:9268-9271 (2000), in which aryl and heteroarylhalides or triflates are reacted with a dialkoxyborane such aspinacolborane, in the presence of Et₃N and Pd(OAc)₂ in dioxane.Compounds of formula (7) and (7a) wherein R₆ is a cycloalkyl ring can beprepared, for example, from cycloalkenes (for example, see H. C. Brown,et al., J. Amer. Chem. Soc., 95:2396-2397 (1973) and H. C. Brown, etal., J. Amer. Chem. Soc., 98:1798-1806 (1976)) or cycloalkyl Grignard orcycloalkyl lithium intermediates (see, for example, Graf et al.,Tetrahedron, 55:8801-8814 (1999) and Michailow, et al., Izv. Akad. NaukSSSR Ser. Khim, 76:78 (1959)).

Reference Example 3 Preparation of Stannane-Type Reagents

Many reagents such as Me₃SnR₆, Bu₃SnR₆, and R₆ZnCl are suitable forreactions under Stille conditions in Scheme 1 and are commerciallyavailable. However, where the reagents wherein R₆ is heteroaryl,heterocyclic, or aryl are not commercially available, they may beprepared by methods available to one with skill in the art. Examples ofsuch methods include lithium halogen-metal exchange of heteroaryl,heterocyclic or aryl halides, followed by treatment with Me₃SnCl (Li, etal. J. Med. Chem. 1996, 39, 1846), Bu₃SnCl, ZnCl₂, or B(OCH₃)₃ (O'Neill,et al. Org. Lett. 2000, 2, 4201; Sindkhedkar, et al. Tet. 2001, 57,2991) and magnesium halogen-metal exchange with isopropylmagnesiumchloride as described in Knochel, et al. J. Org. Chem. 2000, 65,4618-4634, followed by treatment with Me₃SnCl, Bu₃SnCl, or ZnCl₂.Heteroaryl halides and triflates can be treated with trimethylstannylsodium as described in A. O. Koren, et al. J. Med. Chem. 1998, 41, 3690,to give Me₃SnR₆. Heteroaryl halides and triflates can be treated withhexamethyldistannane as described in W. C. Black, et al. J. Med. Chem.1999, 42, 1274., to give Me₃SnR₆.

EXAMPLES Example 14-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrileExample 1A (6-bromo-2-naphthyl)methanol

To a stirred 1.0 M THF solution of lithium aluminum hydride (108 mL, 108mmol) was added dropwise over 20 min a solution of methyl6-bromo-2-naphthoate (18.9 g, 71.3 mmol) in THF (180 mL), whilemaintaining the reaction temperature below −5° C. When the addition wascomplete, the reaction mixture was stirred at −10° C. for 1 hr, thenquenched by the sequential dropwise addition of distilled water (4 mL),2 N aqueous Na₂CO₃ (4 mL), and distilled water (12 mL). After stirringfor 15 min at room temperature, the reaction mixture was filtered. Thefilter cake was washed with ethyl acetate (3×100 mL) and the combinedfiltrates were dried (MgSO₄) and filtered. This filtrate wasconcentrated under reduced pressure to give a white solid. Drying undervacuum overnight at 40° C. provided the product (16.84 g, 99% yield).M.p. 149.9-151.6° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.99 (d, J=2 Hz, 1H),7.79-7.67 (m, 3H), 7.55 (dd, J=2, 12 Hz, 1H), 7.52 (dd, J=2, 12 Hz, 1H),4.85 (s, 2H). MS (DCI-NH₃) [M]⁺ at 236.

Example 1B 2-bromo-6-(chloromethyl)naphthalene

A stirred solution of the product from Example 1A (30.5 g, 129 mmol) indioxane (320 mL) under a dry nitrogen atmosphere was chilled to −10° C.Solid anhydrous ZnCl₂ (514 mg, 3.77 mmol, 0.03 equiv.) was added in onelot, followed by the dropwise addition of thionyl chloride (19.3 mL, 264mmol, 2.0 equiv.). The reaction mixture was allowed to warm to roomtemperature then stirred an additional 2 hr. This reaction mixture wasthen concentrated under reduced pressure and the residue was partitionedbetween dichloromethane and saturated aqueous NaHCO₃ (500 mL). Theorganic layer was washed with brine (2×100 mL), dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure to give awhite solid. Drying under vacuum overnight at 40° C. provided theproduct (32.6 g, 99% yield). M.p. 133.1-134.1° C. ¹H NMR (CDCl₃, 300MHz) δ 8.00 (d, J=2 Hz, 1H), 7.81-7.67 (m, 3H), 7.56 (dd, J=2, 12 Hz,1H), 7.54 (dd, J=2, 12 Hz, 1H), 4.73 (s, 2H). MS (DCI-NH₃) [M]⁺ at 254.

Example 1C (6-bromo-2-naphthyl)acetonitrile

A mixture of the product from Example 1B (32.2 g, 126 mmol) and NaCN(7.44 g, 152 mmol, 1.2 equiv.) in acetonitrile (314 mL) and distilledwater (32 mL) under a dry nitrogen atmosphere was stirred at reflux for21 hr. The reaction mixture was cooled to room temperature thenconcentrated under reduced pressure. The residue was stirred withdistilled water (314 mL) for 45 min. The resulting white solid wasisolated by filtration and washed with distilled water (1500 mL). Dryingunder vacuum overnight at 40° C. provided the product (32.2 g, 97%yield). M.p. 119.6-120.6° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.01 (d, J=2 Hz,1H), 7.82-7.68 (m, 3H), 7.60 (dd, J=2, 12 Hz, 1H), 7.41 (dd, J=2, 12 Hz,1H), 3.90 (s, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 263, [M+NH₄.NH₃]⁺ at 280.

Example 1D (6-bromo-2-naphthyl)acetic acid

A stirred mixture of the product from Example 1C (29.62 g, 120 mmol) inglacial acetic acid (300 mL) and distilled water (150 mL) under a drynitrogen atmosphere was cooled to −15° C. Concentrated sulfuric acid(120 mL, 4.32 mol, 36.0 equiv.) was added dropwise over 20 min whilemaintaining the reaction temperature below 10° C. The reaction mixturewas then stirred at reflux for 2 hr. After cooling to 35° C., ice (500g) was added to the mixture and stirring was continued for 45 min. Theresulting white solid was isolated by filtration and washed withdistilled water (1500 mL). Drying under vacuum overnight at 40° C.provided the product (29.57 g, 93% yield). ¹H NMR (CDCl₃, 300 MHz) δ7.99 (d, J=2 Hz, 1H), 7.76-7.64 (m, 3H), 7.54 (dd, J=2, 12 Hz, 1H), 7.44(dd, J=2, 12 Hz, 1H), 3.81 (s, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 282.

Example 1E 2-(6-bromo-2-naphthyl)ethanol

To a stirred, −15° C. solution of the product from Example 1D (28.6 g,108 mmol) in anhydrous THF (143 mL) under a dry nitrogen atmosphere wasadded dropwise over 15 min a 1.0 M solution of BH₃-THF (409 mL, 409mmol, 3.8 equiv.) while maintaining the reaction temperature below 0° C.When the addition was complete, the reaction mixture was stirred at −15°C. for 15 min, then allowed to warm to room temperature and stirred anadditional 2 hr. The reaction mixture was then cooled to −10° C. andquenched with distilled water (104 mL). After stirring for 15 min atroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was partitioned between dichloromethane (350 mL)and distilled water (200 mL) and the aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic extracts were washedwith distilled water (3×100 mL), dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure to give a white solid.Drying under vacuum overnight at 40° C. provided the product (26.1 g,96% yield). M.p. 102.3-103.1° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=2Hz, 1H), 7.74-7.63 (m, 3H), 7.53 (dd, J=2, 12 Hz, 1H), 7.49 (dd, J=2, 12Hz, 1H), 4.00-3.92 (m, 2H), 3.02 (t, J=6 Hz, 2H), 1.43-1.35 (t_(br), J=6Hz, 1H). MS (DCI-NH₃) [M+NH₄]⁺ at 268.

Example 1F 4-[6-(2-hydroxyethyl)-2-naphthyl]benzonitrile

A mixture of the product from Example 1E (0.60 g, 2.39 mmol),4-cyanophenylboronic acid (0.42 g, 2.87 mmol, 1.2 equiv.), PdCl₂(PPh₃)₂(34 mg, 0.048 mmol, 0.020 equiv.) and K₃PO₄.H₂O (1.38 g, 7.17 mmol, 3.0equiv.) in isopropanol (40 mL) and distilled water (15 mL) was stirredat 65° C. under a dry nitrogen atmosphere for 1.5 hr. The reactionmixture was cooled to room temperature then concentrated under reducedpressure. The residue was partitioned between ethyl acetate and brine.The aqueous layer was washed with ethyl acetate, and the combinedorganic extracts were washed with saturated aqueous NH₄Cl, dried(MgSO₄), and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography (7:3hexane/ethyl acetate). Fractions containing product were combined andconcentrated under reduced pressure to provide the product as anoff-white solid (0.59 g, 90% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.04 (d,J=2 Hz, 1H), 7.93-7.68 (m, 8H), 7.44 (dd, J=2, 12 Hz, 1H), 3.98 (t, J=6Hz, 2H), 3.07 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 291,[M+NH₄.NH₃]⁺ at 308.

Example 1G 2-[6-(4-cyanophenyl)-2-naphthyl]ethyl4-methylbenzenesulfonate

A mixture of the product from Example 1F (0.48 g, 1.76 mmol),p-toluenesulfonyl chloride (0.37 g, 1.93 mmol, 1.1 equiv.), and pyridine(3.0 mL, 37.1 mmol, 21.1 equiv.) in anhydrous dichloromethane (20 mL)was stirred at room temperature under a dry nitrogen atmosphere for 3days. The reaction mixture was concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and 10% aqueous citricacid. The aqueous layer was washed with ethyl acetate, and the combinedorganic extracts were washed with saturated aqueous NaHCO₃, dried(MgSO₄), and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography (6:4dichloromethane/hexane). Fractions containing product were combined andconcentrated under reduced pressure to provide the product as a whitesolid (0.30 g, 40% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.01 (d, J=2 Hz,1H), 7.86-7.75 (m, 6H), 7.72-7.56 (m, 4H), 7.29 (dd, J=2, 12 Hz, 1H),7.17 (d, J=9 Hz, 2H), 4.34 (t, J=6 Hz, 2H), 3.14 (t, J=6 Hz, 2H), 2.36(s, 3H). MS (DCI-NH₃) [M+NH₄]⁺ at 445.

Example 1H4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

A mixture of the product from Example 1G (0.30 g, 1.08 mmol),(2R)-2-methylpyrrolidine (0.30 g, 3.52 mmol, 5.0 equiv.), and cesiumcarbonate (0.70 g, 2.1 mmol, 3.0 equiv.) in anhydrous acetonitrile (5mL) was stirred in a sealed tube at 50° C. under a dry nitrogenatmosphere for 2 days. The reaction mixture was cooled to roomtemperature then concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and saturated aqueous Na₂CO₃. Theaqueous layer was washed with ethyl acetate, and the combined organicextracts were washed with brine, dried (MgSO₄), and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography (95:5:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the productas an off-white solid (0.130 g, 54.4% yield). This solid was dissolvedin methanol and stirred with one equivalent of L-tartaric acid. Thesolvent was removed under reduced pressure to give the tartrate salt ofthe product as a white solid. M.p. 157.4-158.1° C. ¹H NMR (tartrate,CD₃OD, 300 MHz) δ 8.20 (d, J=2 Hz, 1H), 8.01-7.93 (m, 4H), 7.88-7.81 (m,4H), 7.53 (dd, J=2, 12 Hz, 1H), 4.40 (s, 2H), 3.81-3.63 (m, 2H),3.63-3.50 (m, 1H), 3.40-3.20 (m, 4H), 2.40-2.27 (m, 1H), 2.18-2.04 (m,2H), 1.85-1.70 (m, 1H), 1.47 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at341.

Example 2 (2R)-1-[2-(6-bromo-2-naphthyl)ethyl]-2-methylpyrrolidineExample 2A 2-(6-bromo-2-naphthyl)ethyl trifluoromethanesulfonate

To a stirred, 0° C. solution of the product from Example 1E (1.08 g, 4.3mmol) and pyridine (0.46 mL, 5.6 mmol, 1.3 equiv.) in anhydrousdichloromethane (40 mL) was added dropwise trifluoromethane sulfonicacid anhydride (0.87 mL, 5.16 mmol, 1.2 equiv.). The reaction mixturewas stirred at 0° C. for 1 hr, then treated with ice water (20 mL). Theorganic layer was isolated, dried (MgSO₄), and filtered. The filtratewas concentrated under reduced pressure to give an oil that was purifiedby elution through a plug of silica gel with 95:5 hexane/ethyl acetate.Fractions containing product were combined and concentrated underreduced pressure to give the product as an off-white solid (1.34 g, 81%yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.00 (d, J=2 Hz, 1H), 7.77-7.64 (m,3H), 7.56 (dd, J=2, 12 Hz, 1H), 7.35 (dd, J=2, 12 Hz, 1H), 4.73 (t, J=6Hz, 2H), 3.28 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 400,[M+NH₄.NH₃]⁺ at 417.

Example 2B (2R)-1-[2-(6-bromo-2-naphthyl)ethyl]-2-methylpyrrolidine

A mixture of the product from Example 2A (1.34 g, 3.5 mmol),(2R)-2-methylpyrrolidine (0.90 g, 10.57 mmol, 3.0 equiv.), and cesiumcarbonate (3.42 g, 10.49 mmol, 3.0 equiv.) in acetonitrile (15 mL) wasstirred at 50° C. in a sealed tube for 18 hr. The reaction mixture wascooled to room temperature then concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and distilled water. Theorganic layer was washed with brine, then dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure to give a beigesolid that was dissolved in Et₂O. The resulting solution was filteredfree of any insoluble material, then treated with HCl (g) to give awhite precipitate that was collected by filtration. This hydrochloridesalt was dissolved in a minimum of water and sodium hydroxide was addedto bring the pH to 14. This basic aqueous mixture was extracted withEt₂O. The organic layer was dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure to provide the free base product asa white solid (0.90 g, 80.8% yield). M.p. (HCl salt) 247.3-250.7° C. ¹HNMR (free base, CD₃OD, 300 MHz) δ 8.00 (d, J=2 Hz, 1H), 7.77-7.67 (m,3H), 7.52 (dd, J=2, 12 Hz, 1H), 7.42 (dd, J=2, 12 Hz, 1H), 3.32-3.23 (m,1H), 3.18-3.03 (m, 1H), 3.03-2.87 (m, 2H), 2.48-2.24 (m, 3H), 2.07-1.94(m, 1H), 1.86-1.73 (m, 2H), 1.52-1.38 (m, 1H), 1.15 (d, J=6 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 318.

Example 31-[3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)phenyl]ethanoneExample 3A 1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone

A mixture of the product from Example 1E (0.78 g, 3.11 mmol),3-acetylphenylboronic acid (0.61 g, 3.72 mmol, 1.2 equiv.), PdCl₂(PPh₂)₂(0.044 g, 0.062 mmol, 0.02 equiv), and K₃PO₄.H₂O (1.80 g, 9.35 mmol, 3equiv) in isopropanol (40 mL) and distilled water (15 mL) was stirred at65° C. under a dry nitrogen atmosphere for 1.5 hr. The reaction mixturewas cooled to room temperature then concentrated under reduced pressure.The residue was partitioned between ethyl acetate and brine. The aqueouslayer was washed with ethyl acetate, and the combined organic extractswere washed with saturated aqueous NH₄Cl, dried (MgSO₄), and filtered.The filtrate was concentrated under reduced pressure and the residue waspurified by column chromatography (7:3 hexane/ethyl acetate). Fractionscontaining product were combined and concentrated under reduced pressureto provide the product as an off-white solid (0.57 g, 63% yield). ¹H NMR(CD₃OD, 300 MHz) δ 8.31 (s, 1H), 8.05 (s, 1H), 8.92-8.98 (m, 4H),8.72-8.79 (m, 2H), 8.54 (t, J=7 Hz, 1H), 7.4 (d, J=5.7 Hz, 1H), 3.96 (t,J=5.3 Hz, 2H), 3.04 (t, J=5.3 Hz, 2H), 2.67, (s, 3H), 2.48 (bs, 1H). MS(DCI-NH₃) [M+H]⁺ at 291 [M+NH₄]⁺ at 308.

Example 3B 2-[6-(3-acetylphenyl)-2-naphthyl]ethyl methanesulfonate

To a stirred, 0° C. solution of the product from Example 3A (0.44 g,1.49 mmol) and Et₃N (0.30 g, 2.98 mmol, 2.0 equiv), methanesulfonylchloride (0.24 g, 2.09 mmol, 1.4 equiv) was added dropwise via asyringe. After 15 minutes the ice bath was removed and the reactionmixture was stirred at room temperature for 1.5 hours. The reactionmixture was concentrated under reduced pressure. The residue waspartitioned between brine and CH₂Cl₂. The aqueous layer was washed withCH₂Cl₂. The combined organic extracts were dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure to provide theproduct as an off-white solid (0.547 g, 99.6% yield). ¹H NMR (CDCl₃, 300MHz) δ 8.28 (s, 1H), 8.05 (s, 1H), 7.87-7.98 (m, 4H), 7.72-7.79 (m, 2H),7.55 (t, J=5.6 Hz, 1H), 7.38 (d, J=5.6 Hz, 1H), 4.48 (t, J=6 Hz, 2H),3.22 (t, J=6 Hz, 2H), 2.86 (s, 3H), 2.66 (s, 3H). MS (DCI-NH₃) [M+NH₄]⁺at 386.

Example 3C1-[3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)phenyl]ethanone

A mixture of the product from Example 3B (0.55 g, 1.48 mmol),(2R)-2-methylpyrrolidine (0.26 g, 3.05 mmol, 3 equiv), and Cs₂CO₃ (1.16g, 3.56 mmol, 2 equiv) in anhydrous acetonitrile (30 mL) was stirred ina sealed tube at 45° C. for 18 hrs. The reaction mixture was cooled toroom temperature then concentrated under reduced pressure. The residuewas partitioned between ethyl acetate and aqueous 2 N NaOH. The aqueouslayer was washed with ethyl acetate. The combined organic layers weredried (MgSO₄), and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography(95:5:trace dichloromethane/methanol/NH₄OH). Fractions containingproduct were combined and concentrated under reduced pressure to providethe product as an off-white solid (0.115 g, 22% yield). The solid wasdissolved in ether and treated with HCl (g) to provide the HCl salt. ¹HNMR (CD₃OD, 300 MHz) δ 8.31 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.96(s, 1H), 7.89 (s, 1H), 7.87 (d, J=13.3 Hz, 1H), 7.75 (d, J=5.8 Hz, 1H),7.71 (s, 1H), 7.58 (t, J=6.7 Hz, 1H), 7.39 (d, J=5.8 Hz, 1H), 3.2-3.28(m, 1H), 3.1-3.2 (m, 1H), 2.9-3.03 (m, 2H), 2.67 (s, 3H), 2.37-2.47 (m,2H), 2.26 (q, J=7 Hz, 1H), 1.94-2.05 (m, 1H), 1.74-1.85 (m, 2H)1.39-1.52 (m, 1H), 1.17 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 358.

Example 42-[3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)phenyl]-2-propanol

To a mixture of the product from Example 3C (0.68 g, 1.91 mmol) inanhydrous THF (10 mL), was added CH₃MgCl (0.91 g, 7.64 mmol, 4 equiv)dropwise via a syringe. The reaction mixture was stirred at roomtemperature for 18 hrs. The reaction was quenched by the addition ofaqueous K₂HPO₄ (25 mL). The reaction mixture was concentrated underreduced pressure. The residue was partitioned between aqueous 2 N NaOHand ethyl acetate. The aqueous layer was washed with ethyl acetate, andthe combined organic extracts were dried (MgSO₄), and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography (90:10:0.1dichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the productas an off-white solid (0.118 g, 17% yield). The solid was dissolved inether and treated with HCl (g) to provide the HCl salt. ¹H NMR (CD₃OD,300 MHz) δ 8.05 (s, 1H), 7.87-7.9 (m, 3H), 7.42 (d, J=6 Hz, 1H), 7.0 (s,1H), 7.7 (d, J=5.3 Hz, 1H), 7.45-7.49 (m, 1H), 7.42 (s, 1H), 7.4 (s,1H), 3.2-3.28 (m, 1H), 3.1-3.2 (m, 1H), 2.9-3.03 (m, 2H), 2.37-2.47 (m,2H), 2.26 (q, J=7 Hz, 1H), 1.94-2.05 (m, 1H), 1.74-1.85 (m, 2H)1.39-1.52 (m, 1H), 1.61 (s, 6H), 1.17 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 374.

Example 5 6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthonitrile

A mixture of the product from Example 2B (100 mg, 0.314 mmol), zinccyanide (22 mg, 0.188 mmol, 0.6 equiv.), Pd₂(dba)₃ (14 mg, 0.016 mmol,0.05 equiv.), 1,1′-bis(diphenylphosphino)ferrocene (21 mg, 0.038 mmol,0.12 equiv.) in DMF (5 mL) and distilled water (0.05 mL) was stirredunder a dry nitrogen atmosphere at 120° C. for 24 hr. The reactionmixture was cooled to 80° C. and treated with 4:1:4 saturated aqueousNH₄Cl/NH₄OH/water, and stirred overnight while cooling to roomtemperature. The mixture was extracted with ethyl acetate. The organiclayer was washed first with 4:1:5 saturated aqueous NH₄Cl/NH₄OH/water,then with brine. The organic layer was dried (MgSO₄), and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure and the residue wasdissolved in Et₂O. The solution was treated with HCl (g) and the mixturewas concentrated under reduced pressure to provide the hydrochloridesalt of the product as a white solid (51 mg, 43% yield). M.p.187.4-188.6° C. ¹H NMR (CD₃OD, 300 MHz) δ 8.38 (s_(br), 1H), 8.03 (d,J=2 Hz, 1H), 8.00 (d, J=2 Hz, 1H), 7.94 (s_(br), 2H), 7.68 (dd, J=2, 12Hz, 1H), 7.63 (dd, J=2, 12 Hz, 1H), 3.84-3.67 (m, 2H), 3.63-3.48 (m,1H), 3.43-3.19 (m, 4H), 2.43-2.29 (m, 1H), 2.24-2.01 (m, 2H), 1.84-1.68(m, 1H), 1.48 (d, J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 265.

Example 64-(6-{[(2R)-2-methyl-1-pyrrolidinyl]methyl}-2-naphthyl)benzonitrileExample 6A 4-[6-(hydroxymethyl)-2-naphthyl]benzonitrile

A mixture of the product from Example 1A (0.119 g, 0.50 mmol),4-cyanophenylboronic acid (0.088 g, 0.60 mmol, 1.2 equiv.), PdCl₂(PPh₃)₂(7 mg, 0.001 mmol, 0.020 equiv.) and K₃PO₄.H₂O (288 mg, 1.5 mmol, 3.0equiv.) in isopropanol (10 mL) and distilled water (4 mL) was stirred at50° C. under a dry nitrogen atmosphere for 1.5 hr. The reaction mixturewas cooled to room temperature then concentrated under reduced pressure.The residue was partitioned between ethyl acetate and saturated aqueousNH₄Cl. The organic layer was dried (MgSO₄), and filtered. The filtratewas concentrated under reduced pressure and the residue was purified bycolumn chromatography (65:35 hexane/ethyl acetate). Fractions containingproduct were combined and concentrated under reduced pressure to providethe product as a white solid (95 mg, 73% yield). M.p. 174.1-175.5° C. ¹HNMR (CDCl₃, 300 MHz) δ 8.06 (d, J=2 Hz, 1H), 7.97-7.70 (m, 8H), 7.54(dd, J=2, 12 Hz, 1H), 4.90 (d_(br), J=6 Hz, 2H), 1.78 (t_(br), J=6 Hz,1H). MS (DCI-NH₃) [M+NH₄]⁺ at 277, [M+NH₄.NH₃]⁺ at 294.

Example 6B 4-[6-(chloromethyl)-2-naphthyl]benzonitrile

A mixture of the product from Example 6A (90 mg, 0.347 mmol), 0.5 MZnCl₂ in THF (0.21 mL, 0.104 mmol, 0.3 equiv.), and thionyl chloride(0.51 mL, 6.94 mmol, 20.0 equiv.) in dioxane (40 mL) was stirred at roomtemperature under a dry nitrogen atmosphere for 3 hr. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and saturated aqueous Na₂CO₃. Theorganic layer was dried (MgSO₄), and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (95:5 hexane/ethyl acetate). Fractions containingproduct were combined and concentrated under reduced pressure to providethe product as a white solid (91 mg, 94.4% yield). M.p. 147.5-149.2° C.¹H NMR (CDCl₃, 300 MHz) δ 8.05 (d, J=2 Hz, 1H), 7.97-7.90 (m, 2H),7.89-7.84 (m, 1H), 7.84-7.71 (m, 5H), 7.57 (dd, J=2, 12 Hz, 1H), 4.78(s, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 295, [M+NH₄.NH₃]⁺ at 312.

Example 6C4-(6-{[(2R)-2-methyl-1-pyrrolidinyl]methyl}-2-naphthyl)benzonitrile

A mixture of the product from Example 6B (90 mg, 0.324 mmol),(2R)-2-methylpyrrolidine (138 mg, 1.62 mmol, 5.0 equiv.), and cesiumcarbonate (317 mg, 0.972 mmol, 3.0 equiv.) in acetonitrile (10 mL) in asealed tube was stirred at 45° C. for 3 hr then for 2 days at roomtemperature. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between ethyl acetate anddistilled water. The organic layer was dried (MgSO₄), and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure and the residue wasdissolved in Et₂O. The solution was treated with HCl (g) and theprecipitate was collected by filtration to provide the hydrochloridesalt of the product as a white solid (51 mg, 43% yield). M.p.212.6-213.6° C. ¹H NMR (CD₃OD, 300 MHz) δ 8.29 (d, J=2 Hz, 1H),8.15-8.06 (m, 3H), 7.98 (d, J=9 Hz, 2H), 7.93 (dd, J=2, 12 Hz, 1H), 7.86(d, J=9 Hz, 2H), 7.67 (dd, J=2, 12 Hz, 1H), 4.77 (, J=3 Hz, 1H), 4.37(d, J=3 Hz, 1H), 3.75-3.61 (m, 1H), 3.46-3.30 (m, 2H), 2.48-2.35 (m,1H), 2.22-1.92 (m, 2H), 1.86-1.72 (m, 1H), 1.47 (d, J=7 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 327.

Example 73-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrileExample 7A 3-[6-(2-hydroxyethyl)-2-naphthyl]benzonitrile

The title compound was prepared by the method of Example 3A,substituting 3-cyanophenylboronic acid in place of 3-acetylphenylboronicacid (0.21 g, 96% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.03-7.97 (m, 2H),7.97-7.86 (m, 3H), 7.76-7.55 (m, 4H), 7.43 (dd, J=2, 12 Hz, 1H), 3.98(t, J=6 Hz, 2H), 3.07 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 291,[M+NH₄.NH₃]⁺ at 308.

Example 7B 2-[6-(3-cyanophenyl)-2-naphthyl]ethyltrifluoromethanesulfonate

To a stirred, 0° C. solution of the product from Example 7A (0.21 g,0.768 mmol) and pyridine (0.08 mL, 1.0 mmol, 1.3 equiv.) in anhydrousdichloromethane (15 mL) was added dropwise trifluoromethane sulfonicacid anhydride (0.16 mL, 0.922 mmol, 1.2 equiv.). The reaction mixturewas stirred at 0° C. for 30 minutes, then treated with ice water (20mL). The organic layer was isolated, dried (MgSO₄), and filtered. Thefiltrate was concentrated under reduced pressure to give an oil that waspurified by column chromatography (95:5 to 70:30 hexane/ethyl acetate).Fractions containing product were combined and concentrated underreduced pressure to give the product (60 mg, 19% yield). ¹H NMR (CDCl₃,300 MHz) δ 8.02-7.87 (m, 5H), 7.76-7.55 (m, 4H), 7.40 (dd, J=2, 12 Hz,1H), 4.80 (t, J=6 Hz, 2H), 3.32 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+NH₄]⁺at 423.

Example 7C3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 3C,substituting the product from Example 7B for the product from Example 3B(21 mg, 38% yield). M.p. 228.5-231.6° C. ¹H NMR (CD₃OD, 300 MHz) δ 8.23(d, J=2 Hz, 1H), 8.20-8.18 (m, 1H), 8.14-8.09 (m, 1H), 8.04-7.98 (m,2H), 7.90-7.85 (m, 2H), 7.70-7.65 (m, 2H), 7.60 (t, J=7 Hz, 2H), 7.54(dd, J=2, 12 Hz, 1H), 3.81-3.63 (m, 2H), 3.60-3.48 (m, 1H), 3.40-3.13(m, 4H), 2.39-2.24 (m, 1H), 2.18-2.00 (m, 2H), 1.82-1.67 (m, 1H), 1.46(d, J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 341.

Example 84-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine

A mixture of the product from Example 2B (50 mg, 0.157 mmol),4-pyridinylboronic acid (48 mg, 0.393 mmol, 2.5 equiv.), PdCl₂(PPh₃)₂ (6mg, 0.0085 mmol, 0.054 equiv.) and K₃PO₄.H₂O (181 mg, 0.943 mmol, 6.0equiv.) in isopropanol (5 mL) and distilled water (2 mL) was stirred at60° C. under a dry nitrogen atmosphere for 1 hr. The reaction mixturewas cooled to room temperature then concentrated under reduced pressure.The residue was partitioned between ethyl acetate and saturated aqueousNa₂CO₃. The organic layer was dried (MgSO₄), and filtered. The filtratewas concentrated under reduced pressure and the residue was purified bycolumn chromatography (95:5:trace dichloromethane/methanol/NH₄OH).Fractions containing product were combined and concentrated underreduced pressure to provide the product as an off-white solid that wasdissolved in Et₂O and treated with HCl (g). This mixture wasconcentrated under reduced pressure to provide the dihydrochloride saltof the product as an off-white, hygroscopic solid (21 mg, 34% yield). ¹HNMR (CD₃OD, 300 MHz) δ 8.90 (d, J=6 Hz, 2H), 8.63 (d, J=2 Hz, 1H), 8.56(d, J=6 Hz, 2H), 8.15-8.05 (m, 3H), 7.98-7.95 (m, 1H), 7.64 (dd, J=2, 12Hz, 1H), 3.86-3.69 (m, 2H), 3.65-3.50 (m, 1H), 3.45-3.19 (m, 4H),2.44-2.30 (m, 1H), 2.28-2.01 (m, 2H), 1.85-1.70 (m, 1H), 1.50 (d, J=6Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 317.

Example 93-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine

The title compound was prepared by the method in Example 8, substituting3-pyridinylboronic acid in place of 4-pyridinylboronic acid (16 mg, 26%yield). ¹H NMR (CD₃OD, 300 MHz) δ 9.35-9.32 (m, 1H), 9.11-9.06 (m, 1H),8.89-8.85 (m, 1H), 8.41 (d, J=2 Hz, 1H), 8.26-8.20 (m, 1H), 8.08 (t, J=9Hz, 2H), 7.98-7.93 (m, 2H), 7.62 (dd, J=2, 12 Hz, 1H), 3.86-3.69 (m,2H), 3.65-3.49 (m, 1H), 3.45-3.22 (m, 4H), 2.43-2.31 (m, 1H), 2.23-2.01(m, 2H), 1.86-1.71 (m, 1H), 1.51 (d, J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at317.

Example 10(3-fluorophenyl)(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)methanol

A 1.7 M solution of t-butyllithium in pentane (0.41 mL, 0.691 mmol, 2.2equiv.) was added dropwise to a stirred, −78° C. solution of the productfrom Example 2B (100 mg, 0.314 mmol) in anhydrous THF (3 mL). Thereaction mixture was stirred at −78° C. for 20 min then3-fluorobenzaldehyde (0.04 mL, 0.377 mmol, 1.2 equiv.) was addeddropwise to the reaction mixture. After stirring at −78° C. for 10 min,the reaction mixture was allowed to reach room temperature thenpartitioned between ethyl acetate and saturated aqueous Na₂CO₃. Theorganic layer was dried (MgSO₄), and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bypreparative TLC (95:5:trace dichloromethane/methanol/NH₄OH). The bandcontaining product was isolated and eluted with 95:5:tracedichloromethane/methanol/NH₄OH. The resulting solution was concentratedunder reduced pressure to provide the free base product as a white solid(3.2 mg, 2.5% yield). ¹H NMR (CD₃OD, 300 MHz) δ 7.84-7.72 (m, 3H),7.66-7.63 (m, 1H), 7.42-7.26 (m, 3H), 7.22-7.13 (m, 2H), 6.98-6.91 (m,1H), 5.91 (s, 1H), 3.32-3.23 (m, 1H), 3.19-3.09 (m, 2H), 2.51-2.26 (m,3H), 2.06-1.94 (m, 1H), 1.85-1.74 (m, 2H), 1.52-1.38 (m, 1H), 1.15 (d,J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 364.

Example 113,5-dimethyl-4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)isoxazole

The title compound was prepared by the methods of Example 3A-3C,substituting 3,5-dimethyl-4-isoxazolylboronic acid in place of3-acetylphenylboronic acid in Example 3A (38 mg, 12% yield). ¹H NMR(CD₃OD, 300 MHz) δ 7.95 (dd, J=2, 12, 2H), 7.85 (d_(br), J=12 Hz, 2H),7.56-7.45 (m, 2H), 3.84-3.65 (m, 2H), 3.63-3.47 (m, 1H), 3.43-3.15 (m,4H), 2.46 (s, 3H), 2.42-2.26 (m, 1H), 2.30 (s, 3H), 2.21-2.01 (m, 2H),1.84-1.68 (m, 1H), 1.48 (d, J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 335.

Example 124-(6-{2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (2S)-2-pyrrolidinylmethanol in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.51-3.64(m, 2H), 3.2-3.34 (m, 2H), 2.93-3.1 (m, 2H), 2.69-2.75 (m, 2H), 2.4 (q,J=6 Hz, 1H), 1.9-2.4 (m, 1H), 1.95-2.05 (m, 2H), 1.81-1.91 (m, 1H). MS(DCI-NH₃) [M+H]⁺ at 357.

Example 134-(6-{2-[(3R)-3-hydroxy-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (3R)-3-pyrrolidinol in place of (2R)-2-methylpyrrolidine.¹H NMR (CD₃OD, 300 MHz) δ8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m,4H), 7.41 (d. J=6 Hz, 1H), 4.34-4.43 (m, 1H), 2.82-3.08 (m, 6H),2.67-2.78 (m, 1H), 2.61 (d, J=5.7 Hz, 1H), 2.11-2.24 (m, 1H), 1.71-2.03(m, 1H). MS (DCI-NH₃) [M+H]⁺ at 343.

Example 144-{6-[2-(2-isobutyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting 2-isobutylpyrrolidine in place of (2R)-2-methylpyrrolidine.¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m,4H), 7.41 (d. J=6 Hz, 1H), 3.31-3.44 (m, 2H), 2.9-3.11 (m, 2H), 2.4-2.53(m, 2H), 2.31 (q, J=5.7 Hz), 1.9-2.12 (m, 2H), 1.4-1.65 (m, 3H),1.22-1.36 (m, 1H), 0.92 (d, J=5.6 Hz, 3H), 0.87 (d, J=5.6 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 383.

Example 154-{6-[2-(2-isopropyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting 2-isopropylpyrrolidine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.11-3.22(m, 1H), 2.91-3.1 (m, 2H), 2.46-2.62 (m, 1H), 2.41-2.45 (m, 2H),1.8-1.93 (m, 1H), 1.68-1.8 (m, 4H), 1.54-1.63 (m 1H), 0.92 (d, J=5.6 Hz,3H), 0.79 (d, J=5.6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 369.

Example 164-(6-{2-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (3R)—N,N-dimethyl-3-pyrrolidinamine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 2.98-3.08(m, 4H), 2.83-2.95 (m, 3H), 2.72-2.76 (m, 1H) 2.5-2.58 (m, 1H), 2.31 (s,6H), 2.01-2.13 (m, 1H), 1.75-1.85 (m, 1H). MS (DCI-NH₃) [M+H]⁺ at 370.

Example 17 4-{6-[2-(diethylamino)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting diethylamine in place of (2R)-2-methylpyrrolidine. ¹H NMR(CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H),7.41 (d. J=6 Hz, 1H), 3.53 (t, J=3.3 Hz, 2H), 3.31 (q, J=3.6 Hz, 4H),3.22 (t, J=3.3 Hz, 2H), 1.35 (t, J=3.6 Hz, 6H). MS (DCI-NH₃) [M+H]⁺ at329.

Example 18 4-{6-[2-(dimethylamino)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting dimethylamine in place of (2R)-2-methylpyrrolidine. ¹H NMR(CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H),7.41 (d. J=6 Hz, 1H), 3.49-3.54 (t, J=3.3 Hz, 2H), 3.23-3.28 (t, J=3.3Hz, 2H), 2.97 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at 301.

Example 19 4-(6-{2-[ethyl(isopropyl)amino]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting isopropylethylamine in place of (2R)-2-methylpyrrolidine.¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m,4H), 7.41 (d. J=6 Hz, 1H), 3.8-3.87 (m, 1H), 3.1-3.57 (m, 6H), 1.31-1.45(m, 9H). MS (DCI-NH₃) [M+H]⁺ at 343.

Example 204-(6-{2-[tert-butyl(methyl)amino]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting t-butylmethylamine in place of (2R)-2-methylpyrrolidine. ¹HNMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m,4H), 7.41 (d. J=6 Hz, 1H), 3.68-3.75 (m, 1H), 3.3-3.43 (m, 2H),2.31-3.28 (m, 1H), 3.11-3.19 (m, 1H), 2.7 (s, 3H), 1.45 (s, 9H). MS(DCI-NH₃) [M+H]⁺ at 343.

Example 214-(6-{2-[(2S)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (2S)-2-methylpyrrolidine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.34-3.45(m, 1H), 3.24-3.35 (m, 1H), 2.97-3.18 (m, 2H), 2.55-2.78 (m, 3H),2.02-2.15 (m, 1H) 1.82-1.94 (m, 2H), 1.48-1.59 (m, 1H), 1.11 (d, J=6 Hz,3H). MS (DCI-NH₃) [M+H]⁺ at 341.

Example 224-(6-{2-[(2R)-2-methyl-1-piperidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (2R)-2-methylpiperidine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 2.86-3.13(m, 5H), 2.49-2.55 (m, 2H), 1.67-1.81 (m, 4H), 1.33-1.46 (m, 2H), 1.08(d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 355.

Example 234-{6-[2-(2,5-dihydro-1H-pyrrol-1-yl)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting 2,5-dihydro-1H-pyrrole in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 5.83, (s,2H), 3.57 (m, 4H), 2.99 (m, 4H). MS (DCI-NH₃) [M+H]⁺ at 325.

Example 24 4-(6-{2-[methyl(propyl)amino]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting propylmethylamine in place of (2R)-2-methylpyrrolidine. ¹HNMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m,4H), 7.41 (d. J=6 Hz, 1H), 2.94-3.03 (m, 2H), 2.74-2.81 (m, 2H),2.45-2.53 (m, 2H), 2.38 (s, 3H), 1.51-1.65 (m, 2H), 0.91 (t, J=6.3 Hz,3H). MS (DCI-NH₃) [M+H]⁺ at 329.

Example 254-(6-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting 2-(methylamino)ethanol in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.67 (t, J=6Hz, 2H), 2.96-3.04 (m, 2H), 2.90-2.98 (m, 2H), 2.66 (t, J=5.3 Hz, 2H),2.42 (s, 3H). MS (DCI-NH₃) [M+H]⁺ at 331.

Example 265-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyrimidineExample 26A [2-(6-bromo-2-naphthyl)ethoxy](tert-butyl)dimethylsilane

A stirred solution of the product from Example 1E (2.51 g, 10 mmol),imidazole (0.715 g, 10.5 mmol, 1.05 equiv), and DMAP (8 mg, 0.066 mmol,0.0066 equiv.) in anhydrous dichloromethane (65 mL) was chilled at 0° C.under a dry nitrogen atmosphere. A solution of t-butyldimethylsilylchloride in anhydrous dichloromethane (15 mL) was added slowly to thereaction mixture. When the addition was complete, the reaction mixturewas allowed to warm to room temperature and stirred for 18 hr. Anaqueous solution of citric acid (10%) was added to the reaction mixture.The organic layer was washed with brine then dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (100% hexane). Fractionscontaining product were combined and concentrated under reduced pressureto provide the product as a white solid (3.25 g, 89% yield). ¹H NMR(CDCl₃, 300 MHz) δ 7.95 (d, J=2 Hz, 1H), 7.68-7.60 (m, 3H), 7.50 (dd,J=2, 12 Hz, 1H), 7.37 (dd, J=2, 12 Hz, 1H), 3.88 (t, J=6 Hz, 2H), 2.96(t, J=6 Hz, 2H), 1.46 (s, 9H), −0.04 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at365, [M+NH₄]⁺ at 382.

Example 26Btert-butyl(dimethyl){2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]ethoxy}silane

A solution of the product from Example 26A (920 mg, 2.518 mmol),Pd(OAc)₂, (28 mg, 0.126 mmol, 0.05 equiv.),2-(dicyclohexylphosphino)biphenyl (176 mg, 0.504 mmol, 0.2 equiv.), andEt₃N (1.4 mL, 10.07 mmol, 4 equiv.) in dioxane (15 mL) was stirred undera dry nitrogen atmosphere at room temperature. Pinacolborane (1.1 mL,7.553 mmol, 3 equiv.) was added dropwise to the reaction mixture. Whenthe addition was complete, the reaction was stirred at 80° C. for 1 hr.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was partitioned between saturatedaqueous NH₄Cl and Et₂O. The organic layer was dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (98:2 hexane/ethylacetate). Fractions containing product were combined and concentratedunder reduced pressure to give the product as a yellow solid (660 mg,64% yield). NMR (CDCl₃, 300 MHz) δ 8.32 (d, J=2 Hz, 1H), 7.83-7.77 (m,3H), 7.64-7.62 (m, 1H), 7.33 (dd, J=2, 12 Hz, 1H), 4.51 (t, 5.7 J=Hz,2H), 3.22 (t, J=5.7 Hz, 2H), 1.39, (s, 12H), 0.86 (s, 9H), 0.04 (s, 6H).MS (DCI-NH₃) [M+NH₄]⁺ at 430.

Example 26C5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine

A solution of the product from Example 26B (206 mg, 0.5 mmol),5-bromopyrimidine (79.5 mg, 0.5 mmol), Pd(PPh₃)₄ (28.9 mg, 0.025 mmol,0.05 equiv.), and Na₂CO₃ (106 mg, 1 mmol, 2 equiv.) in toluene (10 mL)and distilled water (1.5 mL) was stirred at reflux under a dry nitrogenatmosphere for 3 hr. After cooling to room temperature, the mixture wasconcentrated under reduced pressure and the residue was partitionedbetween ethyl acetate and saturated aqueous Na₂CO₃. The organic layerwas dried (MgSO₄) and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(8:2 hexane/ethyl acetate). Fractions containing product were combinedand concentrated under reduced pressure to give the product as anoff-white solid (57 mg, 31%). ¹H NMR (CDCl₃, 300 MHz) δ 9.23 (s_(br),1H), 9.08 (s_(br), 2H), 8.02 (d, J=2 Hz, 1H), 7.93 (d_(br), J=7 Hz, 1H),7.86 (d_(br), J=7 Hz, 1H), 7.72 (s_(br), 1H), 7.66 (dd, J=2, 12 Hz, 1H),7.44 (dd, J=2.12 Hz, 1H), 3.92 (t, J=6 Hz, 2H), 3.01 (t, J=6 Hz, 2H),0.88 (s, 9H), −0.02 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at 365.

Example 26D 2-[6-(5-pyrimidinyl-1)-2-naphthyl]ethanol

A solution of the product from Example 26C (56 mg, 0.154 mmol) andTBAF.H₂O (48 mg, 0.184 mmol, 1.2 equiv.) in THF (3 mL) was stirred atroom temperature under a dry nitrogen atmosphere for 30 min. The mixturewas then partitioned between ethyl acetate and saturated aqueous Na₂CO₃.The organic layer was washed with brine then dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure to give the titlecompound as an off-white solid (32 mg, 83% yield) which was used in thenext step without further purification.

Example 26E 2-[6-(5-pyrimidinyl)-2-naphthyl]ethyl methanesulfonate

The title compound was prepared by the method of Example 3B,substituting the product from Example 26D in place of the product fromExample 3A to give an off-white solid.

Example 26F5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyrimidine

The title compound was prepared by the method of Example 3C substitutingthe product from Example 26E in place of the product from Example 3B (17mg, 36% yield). ¹H NMR (CD₃OD, 300 MHz) δ 9.35 (s_(br), 2H), 9.28(s_(br), 1H), 8.32 (d, J=2 Hz, 1H), 8.09-8.03 (m, 2H), 7.94-7.88 (m,2H), 7.60-7.55 (m, 1H), 3.85-3.69 (m, 2H), 3.62-3.50 (m, 1H), 3.44-3.18(m, 4H), 2.43-2.30 (m, 1H), 2.27-2.01 (m, 2H), 1.84-1.70 (m, 1H), 1.50(d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 318.

Example 274-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)morpholine

A mixture of the product from Example 2B (318 mg, 1.0 mmol), morpholine(0.87 mL, 1.0 mmol), Pd₂(dba)₃ (18.3 mg, 0.02 mmol, 0.02 equiv.),(t-Bu)₃P (3.6 mg, 0.016 mmol, 0.016 equiv.), and sodium t-butoxide(144.2 mg, 1.5 mmol, 1.5 equiv.) in toluene (2 mL) was stirred at roomtemperature under a dry nitrogen atmosphere for 66 hr. The reactionmixture was partitioned between ethyl acetate and saturated aqueousNa₂CO₃. The organic layer was then washed with brine, dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the productthat was dissolved in Et₂O and treated with HCl (g). This mixture wasconcentrated under reduced pressure to provide the dihydrochloride saltof the product as an off-white, hygroscopic solid (100 mg, 31% yield).¹H NMR (CD₃OD, 300 MHz) δ 8.21 (d, J=6 Hz, 2H), 8.12-8.00 (m, 2H), 7.95(s_(br), 3H), 7.80 (dd, J=2, 12 Hz, 1H), 7.64 (dd, J=2, 12 Hz, 1H),4.18-4.13 (m, 4H), 3.94-3.67 (m, 2H), 3.92-3.87 (m, 4H), 3.63-3.47 (m,1H), 3.47-3.21 (m, 4H), 2.42-2.30 (m, 1H), 2.23-2.00 (m, 2H), 1.85-1.70(m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 325.

Example 282-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)-1,3-thiazoleExample 28A2-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]-1,3-thiazole

The title compound was prepared by the method in Example 26C,substituting 2-bromothiazole in place of 5-bromopyrimidine (40 mg, 22%yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.44 (d, J=2 Hz, 1H), 8.07 (dd, J=2,12 Hz, 1H), 7.93 (d, J=3 Hz, 1H), 7.19-7.84 (m, 2H), 7.70-7.68 (m, 1H),7.42 (dd, J=2, 12, 1H), 7.38 (d, J=3 Hz, 1H), 3.93 (t, J=6 Hz, 2H), 3.02(t, J=6 Hz, 2H), 0.89 (s, 9H), 0.02 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at 370.

Example 28B 2-[6-(1,3-thiazol-2-yl)-2-naphthyl]ethanol

The title compound was prepared by the method in Example 26D,substituting the product from Example 28A in place of the product fromExample 26C.

Example 28C 2-[6-(1,3-thiazol-2-yl)-2-naphthyl]ethyl methanesulfonate

The title compound was prepared by the method of Example 3B,substituting the product from Example 28B in place of the product fromExample 3A to give an off-white solid.

Example 28D2-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)-1,3-thiazole

The title compound was prepared by the method of Example 3C substitutingthe product from Example 28C in place of the product from Example 3B(hydrochloride salt, 4 mg, 14% yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.55(d, J=2 Hz, 1H), 8.12 (d, J=3 Hz, 1H), 8.10-8.02 (m, 3H), 7.95-7.92 (m,1H), 7.89 (d, J=3 Hz, 1H), 7.61 (dd, J=2, 12 Hz, 1H), 3.84-3.69 (m, 2H),3.64-3.49 (m, 1H), 3.43-3.19 (m, 4H), 2.43-2.30 (m, 1H), 2.23-2.00 (m,2H), 1.83-1.69 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at323.

Example 294-(6-{2-[(2S)-2-(fluoromethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (2S)-2-(fluoromethyl)pyrrolidine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 4.44 (d,J=1.3 Hz, 1H), 4.28 (d, J=1.3 Hz, 1H), 3.18-3.35 (m, 2H), 2.98-3.06 (m,2H), 2.84-2.99 (m, 1H), 2.69-2.78 (M, 1H), 2.41-2.53 (m, 1H), 1.92-2.03(m, 1H), 1.75-1.88 (m, 2H), 1.58-1.7 (m, 1H). MS (DCI-NH₃) [M+H]⁺ at359.

Example 30(3-fluorophenyl)(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)methanone

A mixture of the product from Example 10 (3.2 mg, 0.009 mmol) andmanganese dioxide (5.4 mg, 0.062 mmol, 7 equiv.) in anhydrousdichloromethane (1 mL) was stirred at room temperature for 3.5 hr. Thereaction mixture was filtered through diatomaceous earth and thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative TLC (95:5:trace dichloromethane/methanol/NH₄OH).The band containing product was isolated and eluted with 95:5:tracedichloromethane/methanol/NH₄OH. The resulting solution was concentratedunder reduced pressure to provide the free base product (0.91 mg, 28.5%yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.27 (d, J=2 Hz, 1H), 8.02-7.86 (m,4H), 7.65-7.51 (m, 4H), 7.46-7.39 (m, 1H), 3.56-3.37 (m, 2H), 3.26-3.07(m, 2H), 3.02-2.74 (m, 2H), 2.21-2.10 (m, 1H), 2.02-1.88 (m, 2H),1.69-1.52 (m, 2H), 1.30 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 362.

Example 312-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-oneExample 31A (6-Bromo-naphthalen-2-yl)-methanol

To a stirred 1.0 M solution of lithium aluminum hydride (108 mL, 108mmol) was added dropwise over 20 min a solution of methyl6-bromo-2-naphthoate (18.9 g, 71.3 mmol) in THF (180 mL), whilemaintaining the reaction temperature below −5° C. When the addition wascomplete, the reaction mixture was stirred at −10° C. for 1 hr, thenquenched by the sequential dropwise addition of distilled water (4 mL),2 N aqueous Na₂CO₃ (4 mL), and distilled water (12 mL). After stirringfor 15 min at room temperature, the reaction mixture was filtered. Thefilter cake was washed with ethyl acetate (3×100 mL) and the combinedfiltrates were dried (MgSO₄) and filtered. This filtrate wasconcentrated under reduced pressure to give a white solid. Drying undervacuum overnight at 40° C. provided the product (16.84 g, 99% yield).M.p. 149.9-151.6° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.99 (d, J=2 Hz, 1H),7.79-7.67 (m, 3H), 7.55 (dd, J=2, 12 Hz, 1H), 7.52 (dd, J=2, 12 Hz, 1H),4.85 (s, 2H). MS (DCI-NH₃) [M]⁺ at 236.

Example 31B 2-Bromo-6-chloromethyl-naphthalene

A stirred solution of the product from Example 31A (30.5 g, 129 mmol) indioxane (320 mL) under a dry nitrogen atmosphere was chilled to −10° C.Solid anhydrous ZnCl₂ (514 mg, 3.77 mmol, 0.03 equiv.) was added in onelot, followed by the dropwise addition of thionyl chloride (19.3 mL, 264mmol, 2.0 equiv.). The reaction mixture was allowed to warm to roomtemperature then stirred an additional 2 hr. This reaction mixture wasthen concentrated under reduced pressure and the residue was partitionedbetween dichloromethane and saturated aqueous NaHCO₃ (500 mL). Theorganic layer was washed with brine (2×100 mL), dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure to give awhite solid. Drying under vacuum overnight at 40° C. provided theproduct (32.6 g, 99% yield). M.p. 133.1-134.1° C. ¹H NMR (CDCl₃, 300MHz) δ 8.00 (d, J=2 Hz, 1H), 7.81-7.67 (m, 3H), 7.56 (dd, J=2, 12 Hz,1H), 7.54 (dd, J=2, 12 Hz, 1H), 4.73 (s, 2H). MS (DCI-NH₃) [M]⁺ at 254.

Example 31C (6-Bromo-naphthalen-2-yl)-acetonitrile

A mixture of the product from Example 31B (32.2 g, 126 mmol) and NaCN(7.44 g, 152 mmol, 1.2 equiv.) in acetonitrile (314 mL) and distilledwater (32 mL) under a dry nitrogen atmosphere was stirred at reflux for21 hr. The reaction mixture was cooled to room temperature thenconcentrated under reduced pressure. The residue was stirred withdistilled water (314 mL) for 45 min. The resulting white solid wasisolated by filtration and washed with distilled water (1500 mL). Dryingunder vacuum overnight at 40° C. provided the product (32.2 g, 97%yield). M.p. 119.6-120.6° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.01 (d, J=2 Hz,1H), 7.82-7.68 (m, 3H), 7.60 (dd, J=2, 12 Hz, 1H), 7.41 (dd, J=2, 12 Hz,1H), 3.90 (s, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 263, [M+NH₄.NH₃]⁺ at 280.

Example 31D (6-Bromo-naphthalen-2-yl)-acetic acid

A stirred mixture of the product from Example 31C (29.62 g, 120 mmol) inglacial acetic acid (300 mL) and distilled water (150 mL) under a drynitrogen atmosphere was cooled to −15° C. Concentrated sulfuric acid(120 mL, 4.32 mol, 36.0 equiv.) was added dropwise over 20 min whilemaintaining the reaction temperature below 10° C. The reaction mixturewas then stirred at reflux for 2 hr. After cooling to 35° C., ice (500g) was added to the mixture and stirring was continued for 45 min. Theresulting white solid was isolated by filtration and washed withdistilled water (1500 mL). Drying under vacuum overnight at 40° C.provided the product (29.57 g, 93% yield). ¹H NMR (CDCl₃, 300 MHz) δ7.99 (d, J=2 Hz, 1H), 7.76-7.64 (m, 3H), 7.54 (dd, J=2, 12 Hz, 1H), 7.44(dd, J=2, 12 Hz, 1H), 3.81 (s, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 282.

Example 31E 2-(6-Bromo-naphthalen-2-yl)-ethanol

To a stirred, −15° C. solution of the product from Example 31D (28.6 g,108 mmol) in anhydrous THF (143 mL) under a dry nitrogen atmosphere wasadded dropwise over 15 min a 1.0 M solution of BH₃-THF (409 mL, 409mmol, 3.8 equiv.) while maintaining the reaction temperature below 0° C.When the addition was complete, the reaction mixture was stirred at −15°C. for 15 min, then allowed to warm to room temperature and stirred anadditional 2 hr. The reaction mixture was then cooled to −10° C. andquenched with distilled water (104 mL). After stirring for 15 min atroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was partitioned between dichloromethane (350 mL)and distilled water (200 mL) and the aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic extracts were washedwith distilled water (3×100 mL), dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure to give a white solid.Drying under vacuum overnight at 40° C. provided the product (26.1 g,96% yield). M.p. 102.3-103.1° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.98 (d, J=2Hz, 1H), 7.74-7.63 (m, 3H), 7.53 (dd, J=2, 12 Hz, 1H), 7.49 (dd, J=2, 12Hz, 1H), 4.00-3.92 (m, 2H), 3.02 (t, J=6 Hz, 2H), 1.43-1.35 (t_(br), J=6Hz, 1H). MS (DCI-NH₃) [M+NH₄]⁺ at 268.

Example 31F 2-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one

A mixture of the product from Example 31E (500 mg, 1.87 mmol),2H-pyridazin-3-one (180 mg, 1.87 mmol), copper powder (120 mg, 1.87mmol), and K₂CO₃ (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 mL) wasstirred at reflux under a dry nitrogen atmosphere for 20 hr. Thereaction mixture was cooled to room temperature then concentrated underreduced pressure. Residual pyridine was removed by repeated evaporationwith toluene. The residue was partitioned between ethyl acetate (350 mL)and saturated aqueous Na₂CO₃. The organic layer was washed twice withaqueous NH₄OH, dried (MgSO₄), filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (75:25 ethyl acetate/hexane) to provide the titlecompound (270 mg, 54% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (d, J=2 Hz,1H), 7.97-7.93 (m, 1H), 7.88 (t, J=9 Hz, 2H), 7.75-7.68 (m, 2H), 7.41(dd, J=2, 12 Hz, 1H), 7.31-7.24 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H), 3.97(t, J=6 Hz, 2H), 3.06 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 267,[M+NH₄]⁺ at 284.

Example 31G Methanesulfonic acid2-[6-(6-oxo-6H-pyridazin-1-yl)-naphthalen-2-yl]-ethyl ester

Methanesulfonyl chloride (0.10 mL, 1.33 mmol, 1.3 equiv.) was addeddropwise via a syringe to a stirred, 0° C. solution of the product fromExample 31F (0.27 g, 1.01 mmol) and Et₃N (0.28 mL, 2.02 mmol, 2.0equiv.). After one hour the ice bath was removed and the reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure. The residue waspartitioned between EtOAc and saturated aqueous Na₂CO₃. The aqueouslayer was extracted with EtOAc. The combined organic extracts were dried(MgSO₄) and filtered. The filtrate was concentrated under reducedpressure then filtered through a pad of silica gel with EtOAc followedby a second removal of solvent to provide the title intermediate as anoff-white solid (300 mg, 87% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.12 (d,J=2 Hz, 1H), 7.97-7.94 (m, 1H), 7.89 (t, J=9 Hz, 2H), 7.76-7.71 (m, 2H),7.41 (dd, J=2, 12 Hz, 1H), 7.31-7.25 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H),4.53 (t, J=6 Hz, 2H), 3.24 (t, J=6 Hz, 2H), 2.83 (s, 3H). MS (DCI-NH₃)[M+H]⁺ at 345, [M+NH₄]⁺ at 362.

Example 31H2-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one

A mixture of the product from Example 31G (0.30 g, 0.87 mmol) and(2R)-2-methylpyrrolidine (0.37 g, 4.36 mmol, 5.0 equiv.) in anhydrousacetonitrile (3.5 mL) was stirred in a sealed tube at room temperaturefor 66 hours. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between ethyl acetate andsaturated aqueous Na₂CO₃. The aqueous layer was extracted with ethylacetate, and the combined organic extracts were dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the freebase product (220 mg, 75.7% yield). The free base was dissolved in Et₂Oand HCl gas was bubbled in until pH 2 was achieved. The resultingprecipitate was crystallized from MeOH/Et₂O to give the hydrochloridesalt. M.p. 198.9-201.5° C. ¹H NMR (CD₃OD, 300 MHz) δ 8.12-8.07 (m, 2H),8.00-7.88 (m, 3H), 7.68 (dd, J=2, 12 Hz, 1H), 7.57-7.49 (m, 2H), 7.13(dd, J=2, 12 Hz, 1H), 3.84-3.64 (m, 2H), 3.64-3.46 (m, 1H), 3.46-3.13(m, 4H), 2.43-2.26 (m, 1H), 2.22-1.99 (m, 2H), 1.85-1.67 (m, 1H), 1.48(d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 334.

Example 322-methoxy-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)pyridine

The title compound was prepared by the method in Example 8, substituting6-methoxy-3-pyridinylboronic acid in place of 4-pyridinylboronic acid(37 mg, 24% yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.50 (d, J=2 Hz, 1H),8.10-8.05 (m, 2H), 7.98-7.92 (m, 2H), 7.85-7.83 (m, 1H), 7.75 (dd, J=2,10 Hz, 1H), 7.50 (dd, J=2.12 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 4.43 (s,2H), 3.97 (s, 3H), 3.81-3.47 (m, 3H), 3.42-3.17 (m, 4H), 2.41-2.28 (m,1H), 2.26-2.04 (m, 2H), 1.85-1.71 (m, 1H), 1.47 (d, J=6 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 347.

Example 334-(6-{2-[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]ethyl}-2-naphthyl)benzonitrile

The title compound was prepared by the method of Example 1H,substituting (2R)-2-pyrrolidinylmethanol in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.51-3.64(m, 2H), 3.2-3.34 (m, 2H), 2.93-3.1 (m, 2H), 2.69-2.75 (m, 2H), 2.4 (q,J=6 Hz, 1H), 1.9-2.4 (m, 1H), 1.95-2.05 (m, 2H), 1.81-1.91 (m, 1H). MS(DCI-NH₃) [M+H]⁺ at 357.

Example 344-{6-[2-(2-methyl-1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting rac-2-methylpyrrolidine in place of(2R)-2-methylpyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 8.13 (s, 1H),7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H), 7.41 (d. J=6 Hz, 1H), 3.68-3.83(m, 2H), 3.51-3.61 (m, 1H), 3.17-3.42 (m, 4H), 2.3-2.43 (m, 1H),2.02-2.12 (m, 2H), 1.68-1.82 (m, 1H), 1.44 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 341.

Example 35 4-{6-[2-(1-pyrrolidinyl)ethyl]-2-naphthyl}benzonitrile

The title compound was prepared by the method of Example 1H,substituting pyrrolidine in place of (2R)-2-methylpyrrolidine. ¹H NMR(CD₃OD, 300 MHz) δ 8.13 (s, 1H), 7.87-7.96 (m, 4H), 7.71-7.85 (m, 4H),7.41 (d. J=6 Hz, 1H), 3.56-3.62 (m, 1H), 3.1-3.18 (m, 1H), 2.84-2.91 (m,1H), 2.75-2.8 (m, 1H), 2.66-2.73 (m, 4H), 1.84-1.9 (m, 4H). MS (DCI-NH₃)[M+H]⁺ at 327.

Example 364-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-naphthyl)thiomorpholine

The title compound was prepared by the method of Example 27,substituting thiomorpholine in place of morpholine. ¹H NMR (CD₃OD, 300MHz) δ 7.62-7.69 (m, 2H), 7.53 (s, 1H), 7.21-7.3 (m, 2H), 7.13 (s, 1H),3.53 (m, 4H), 3.23-4.0 (m, 1H), 3.06-3.16 (m, 1H), 2.82-3.01 (m, 2H),2.73 (m, 4H), 2.25-2.48 (m, 3H), 1.94-2.04 (m, 1H), 1.72-1.84 (m, 2H),1.38-1.41 (m, 1H), 1.11 (d, J=6 Hz, 3H). MS (DCI-NH₃) (M+H)⁺ at 341.

Example 37 1-{2-[(6-bromo-2-naphthyl)oxy]ethyl}pyrrolidine Example 37A2-bromo-6-(2-bromoethoxy)naphthalene

A round-bottom flask containing 1.0 g (4.5 mmol) of 6-bromo-2-naphthol,1,2-dibromoethane (135 mmol, 12 mL), potassium hydroxide (5 mL of a 40%solution) and tetrabutylammonium bromide (1.35 mmol, 0.43 g) was heatedat 100° C. for 3 h. The reaction mixture was diluted with 150 mL ofCH₂Cl₂ and washed with water and brine, dried over sodium sulfate andconcentrated under vacuum to give the desired compound in 100% as a palebrown solid; ¹HNMR (300 MHz, CDCl₃) δ 3.70 (t, 2H), 4.40 (t, 2H),7.05-7.90 (m, 6H). MS (DCI) m/z 330 (M⁺).

Example 37B 1-{2-[(6-bromo-2-naphthyl)oxy]ethyl}pyrrolidine

In a flask containing 0.5 g (1.5 mmol) the product from Example 37A, 10mL of pyrrolidine was added. After stirring at 80° C. for 3 h, thereaction mixture was concentrated under vacuum. The residue was dilutedwith 100 mL of CH₂Cl₂ and washed sequentially with water, sodiumbicarbonate and brine, dried and evaporated under reduced pressure.Silica gel chromatography (MeOH:CH₂Cl₂, 95:5) gave the desired materialin 98% yield. ¹HNMR (300 MHz, CDCl₃) δ 1.80 (m, 4H), 2.6 (m, 4H), 2.97(t, 2H), 4.20 (t, 2H), 2.49 (m, 2H) 7.10-7.90 (m, 6H); MS (ESI) m/z 321(M+H)⁺.

Example 38 3-{6-[2-(1-pyrrolidinyl)ethoxy]-2-naphthyl}benzonitrile

A mixture of the product from Example 37B (35 mg, 0.11 mmol),3-cyanophenylboronic acid (22 mg, 0.15 mmol), PdCl₂(PPh₃)₂ (4.2 mg, 6μmol), and isopropanol (0.5 mL) was treated with 2 M aqueous sodiumcarbonate (80 μL) and heated at 85° C. overnight. The mixture was cooledto room temperature and partitioned between 2 M aqueous NaOH anddichloromethane. The aqueous phase was separated and extracted withdichloromethane. The combined organic phases were filtered throughdiatomaceous earth, concentrated, and chromatographed through silicawith a gradient of 0%/50%/50% to 10%/40%/50% methanol/ethylacetate/dichloromethane followed by 8% methanol/dichloromethane toprovide the title compound. ¹HNMR (300 MHz, CD₃OD) δ 1.86 (m, 4H), 2.73(m, 4H), 3.01 (t, 2H), 4.28 (t, 2H), 7.22 (dd, 1H), 7.31 (d, 1H), 7.65(t, 1H), 7.70 (dt, 1H), 7.75 (dd, 1H), 7.85-7.92 (m, 2H), 8.06 (dt, 1H),8.07-8.13 (m, 2H); MS (ESI) m/z 343 (M+H)⁺.

Example 39 3-{6-[2-(1-pyrrolidinyl)ethoxyl]-2-naphthyl}pyridine

The product from Example 37B and3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine were processedas described in Example 38, except that a second column chromatographywas done to provide 10 mg of the title compound. ¹HNMR (300 MHz, CD₃OD)δ 1.86 (m, 4H), 2.74 (m, 4H), 3.02 (t, 2H), 4.29 (t, 2H), 7.23 (dd, 1H),7.31 (d, 1H), 7.56 (ddd, 1H), 7.76 (dd, 1H), 7.86-7.93 (m, 2H), 8.10 (d,1H), 8.20 (ddd, 1H), 8.52 (dd, 1H), 8.91 (dd, 1H); MS (ESI) m/z 319(M+H)⁺.

Example 403-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy}-2-naphthyl)benzonitrileExample 40A(2R)-1-{2-[(6-bromo-2-naphthyl)oxy]ethyl}-2-methylpyrrolidine

((2R)-2-Methylpyrrolidine (L)-tartrate (541 mg, 2.3 mmol) waspartitioned between aqueous 2 M NaOH (2.5 mL) and toluene (0.6 mL). Theaqueous phase was separated, diluted with brine (0.3 mL), and extractedwith toluene (2×0.3 mL). The combined organic phases were dried (Na₂SO₄)and carried on to the next step with a toluene rinse (0.3 mL).

The product from Example 37A (495 mg, 1.5 mmol), potassium carbonate(207 mg, 1.5 mmol), and the above toluene solution were suspended intoDMF (3 mL) and heated at 50° C. overnight. The reaction mixture wasbrought to room temperature and partitioned between 0.2 M aqueous NaOH(20 mL) and dichloromethane (10 mL). The aqueous phase was separated andextracted with dichloromethane, and the combined organic phases werewashed with 0.2 M aqueous NaOH, dried (Na₂SO₄), and filtered quicklythrough a silica plug with a 0 to 10% methanol/dichloromethane gradient.The filtrate was partitioned between water and 2:1dichloromethane/hexanes. The aqueous phase was separated and extractedwith 20% hexanes/dichloromethane, and the combined organic phases wereconcentrated and chromatographed through silica with a littlehexanes/dichloromethane followed by a gradient of 0 to 10%methanol/dichloromethane. The appropriate fractions were combined andconcentrated under high vacuum to provide 451 mg of a 6:1 mixture oftitle compound and starting dibromide which was used in the next stepwithout further purification; MS (ESI APCl) m/z 334/336 (M+H)⁺.

Example 40B3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy}-2-naphthyl)benzonitrile

A mixture of the product from Example 40A (147 mg, approximately 0.38mmol), 3-cyanophenylboronic acid (96 mg, 0.65 mmol), PdCl₂(PPh₃)₂ (28mg, 0.04 mmol) and isopropanol (2.5 mL) was treated with 2 M aqueoussodium carbonate (700 μL) and heated at 55° C. overnight, then at 85° C.for two days. The mixture was cooled to room temperature and partitionedbetween 2 M aqueous NaOH (2 mL) and dichloromethane (10 mL). The aqueousphase was separated and extracted with dichloromethane. The combinedorganic phases were filtered through diatomaceous earth, concentrated,and chromatographed through silica once with a gradient of 0%/50%/50% to10%140%150% methanol/ethyl acetate/dichloromethane, and a second timewith a gradient of 0%/0%/100% to 0%150%150% to 5%145%150% methanol/ethylacetate/dichloromethane to provide 28 mg of an orange gum; ¹HNMR (300MHz, CD₃OD) δ 1.10 (d, 3H), 1.48 (m, 1H), 1.75-1.88 (m, 2H), 2.01 (m,1H), 2.40 (m, 1H), 2.53 (m, 1H), 2.65 (m, 1H), 3.23-3.38 (m, 2H),4.22-4.34 (m, 2H), 7.22 (dd, 1H), 7.30 (d, 1H), 7.65 (t, 1H), 7.70 (dt,1H), 7.75 (dd, 1H), 7.85-7.92 (m, 2H), 8.06 (dt, 1H), 8.07-8.12 (m, 2H);MS (ESI) m/z 357 (M+H)⁺.

Example 413-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy}-2-naphthyl)pyridine

The product from Example 40A and3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine were processedas described for Example 40B, except that a single chromatography wasconducted with a gradient of 0%/50%/50% to 10%/40%/50% methanol/ethylacetate/dichloromethane followed by 8% methanol/dichloromethane toprovide the title compound. ¹HNMR (300 MHz, CD₃OD) δ 1.10 (d, 3H), 1.47(m, 1H), 1.75-1.88 (m, 2H), 2.02 (m, 1H), 2.41 (m, 1H), 2.54 (m, 1H),2.66 (m, 1H), 3.22-3.39 (m, 2H), 4.24-4.33 (m, 2H), 7.22 (dd, 1H), 7.31(d, 1H), 7.55 (ddd, 1H), 7.76 (dd, 1H), 7.86-7.94 (m, 2H), 8.10 (d, 1H),8.21 (ddd, 1H), 8.52 (dd, 1H), 8.91 (dd, 1H); MS (ESI) m/z 333 (M+H)⁺.

Example 424-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)benzonitrileExample 42A ethyl (6-bromo-2-Quinolinyl)acetate

To a solution of diisopropylamine (19.2 g, 0.19 mole) in diethyl ether(200 mL) was added 2.5 M n-butyllithium in hexane (74 mL, 0.185 mole) at−78° C. The clear solution was mixed for 30 min, and followed byaddition of 6-bromo-2-methyl-quinoline (13.32 g, 0.060 mole) in ether(200 mL) slowly at −78° C. The brown solution was stirred for 0.5 hour,and ethyl chloroformate (7.45 g, 0.069 mole) in ether (50 mL) wassyringed into the mixture slowly so that the internal temperature didnot exceed −70° C. The yellow reaction mixture was quenched by additionof 50 mL water, allowed to warm up to rt, and diluted with ethyl acetate(300 mL). The solution was washed with 5% sodium bicarbonate aq.solution (700 mL×3), 25% brine (700 mL), dried over MgSO₄, and filtered.The organic was concentrated to ˜50 mL volume, and the slurry dilutedwith heptane (50 mL). The slurry was stirred at 0° C. for 2 h, and thesolid was collected by filtration, rinsed with a ice-cold heptane: ethylacetate (10 mL, 2:1), dried at 50° C. under vacuum to give a yellowsolid (12.0 g). Concentration of the mother liquid afforded a 2^(nd)crop of the product (3.6 g). Total yield: 88%; mp: 100-101° C.(uncorrected); MS (ESI): 294, 296 (M+H)⁺; ¹H-NMR (CDCl₃) δ 8.02 (1H, d,J=8.5 Hz), 7.94 (1H, d, J=2.2 Hz), 7.91 (1H, d, J=8.9 Hz), 7.74 (1H, dd,J=8.9, 2.2 Hz), 7.44 (1H, d, J=8.5 Hz), 4.20 (2H, q, J=7.1 Hz), 4.01(2H, s), 1.27 (3H, t, J=7.1 Hz); ¹³C-NMR (CDCl₃) δ 169.7, 154.9, 146.0,135.1, 132.6, 130.5, 128.9, 127.8, 122.3, 119.9, 61.2, 44.9, 14.5.

Example 42B 2-(6-bromo-2-quinolinyl)ethanol

A 1 L round bottom flask was charged with the product from Example 42A(12.0 g, 0.0408 mole), lithium borohydride (1.78 g, 0.00816 mole) andTHF (450 mL) under a nitrogen atmosphere. Ethanol (18.8 g, 0.408 mole)was added slowly at <25° C., and the yellow mixture stirred at rt for 4hours. Methanol (40 mL) was carefully added and the mixture wasconcentrated to ˜50 mL of volume. The mixture was diluted with ethylacetate (250 mL), washed with 5% NaHCO₃ aq. solution, and water (300mL). The organic layer was concentrated, azeotroped with ethyl acetate(250 mL×2) to a volume of ˜50 mL. The resulting precipitate was dilutedwith heptane (50 mL), stirred at room temperature overnight, and then at5° C. for 2 hours. The solid was filtered, rinsed with heptane (20 mL),and dried at 50° C. to give 7.70 g of the product (75% yield); mp:103-104° C. (uncorrected); MS (ESI): 251, 253 (M+H)⁺; ¹H-NMR (CDCl₃) δ7.96 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=2.2 Hz), 7.84 (1H, d, J=8.9 Hz),7.72 (1H, dd, J=8.9, 2.2 Hz), 7.27 (1H, d, J=8.4 Hz), 4.13 (2H, d, J=5.6Hz), 3.19 (2H, d, J=5.6 Hz); ¹³C-NMR (CDCl₃) δ 161.3, 145.4, 135.1,132.6, 130.1, 129.2, 127.5, 122.4, 119.5, 61.2, 39.7.

Example 42C 2-(6-bromo-2-quinolinyl)ethyl 4-methylbenzenesulfonate

A 500 mL round bottom flask was charged with the product from Example42B (7.65 g, 0.030 mole), 4-N,N-dimethylaminopyridine (0.36 g, 0.003mole), dichloromethane (100 mL) and triethylamine (9.3 g, 0.092 mmol).p-Toluenesulfonyl chloride (11.5 g, 0.060 mole) was added in portions,and the solution was stirred at rt for 6 hours. The solution wasstripped down to dryness, and the crude product was taken into ethylacetate (150 mL) and 5% NaHCO₃ aq. solution (150 mL). The upper organicwas washed with water (150 mL), concentrated, azeotroped with ethylacetate (250 mL×2) to a volume of ˜50 mL. The slurry was diluted withheptane (50 mL), stirred at room temperature overnight, and then at 5°C. for 8 hours. The precipitate was collected by filtration, rinsed withheptane (20 mL), dried at 50° C. under vacuum overnight to afford 10.80g of the product as an off-white solid; mp 107-109° C.; MS (ESI): 406,408 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.92 (1H, m), 7.91 (1H, m), 7.7 (2H, m),7.58 (2H, m), 7.25 (1H, d, J=8.4 Hz), 7.09 (2H, m), 4.56 (2H, t, J=6.3Hz), 3.27 (2H, t, J=6.3 Hz), 2.33 (3H, s); ¹³C-NMR (CDCl3) δ 157.2,145.9, 144.1, 135.0, 132.5, 132.3, 130.3, 129.2, 129.2, 127.7, 127.4,122.5, 119.6, 69.2, 38.0, 21.8.

Example 42D 6-bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled),potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile (190mL) were combined and heated at 60° C. with agitation for 48 hours. Themixture was allowed to cool to 30° C., and treated with the product fromExample 42C (8.00 g, 0.0197 mole). The reaction mixture was heated at−60° C. for 36 hours and then distilled down to ˜1/4 volume, andisopropyl acetate (200 mL) was added. The mixture was washed with 5%NaHCO₃ aq. solution (200 mL×2), and 25% brine (200 mL). The upperorganic was dried over anhydrous sodium sulphate, filtered, and thefiltrate was concentrated to dryness. The crude product was purifiedwith a short-path silica gel column eluted with heptane:ethylacetate:TEA (60:40:1) to give 5.8 g (92% yield) of product as an oil,which solidified on standing; mp 49-50° C. (uncorrected); MS (ESI): 319,311 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.95 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2.2Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz), 7.35 (1H, d,J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m), 2.38 (1H, m), 2.25(1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H,m), 1.11 (3H, d, J=6.0 Hz); ¹³C-NMR (CDCl₃) δ 161.3, 146.1, 134.7,132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0,22.0, 19.4.

Example 42E4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)benzonitrile

The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronicacid (0.75 mmol), and dichlorobis(triphenylphosphine) palladium (II)(35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2M K₃PO₄ aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24hours. The reaction mixture was allowed to cool to room temperature anddiluted with ethyl acetate (20 mL). The organic phase was separated,washed with 5% NaHCO₃ (25 mL×3), 25% brine (25 mL), dried over Na₂SO₄,filtered, and the filtrate concentrated to dryness. The residue waspurified by column chromatography (heptane:acetone:CH₂Cl₂:TEA(60:40:5:1) to provide the title compound. The title compound wastreated with one equivalent of L-tartaric acid in IPA:ethanol to givethe tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)⁺; ¹H NMR (DMSO-d₆) δ8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d),7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m),3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m),1.55 (1H, m), 1.29 (3H, d).

Example 436-(4-fluorophenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example42E substituting 4-fluorophenylboronic acid for 4-cyanophenylboronicacid. The title compound was treated with HCl in IPA:ethyl acetate togive the dihydrochloride salt. mp 145° C.; MS (ESI) 335 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 8.88 (1H, d), 8.5 (1H, br), 8.42 (1H, d), 8.37 (1H, d), 7.97(1H, d), 7.91 (2H, dd), 7.40 (2H, t), 3.93 (1H, br), 3.72 (3H, br), 3.5(2H, br), 3.26 (1H, br), 2.2 (1H, m), 2.0 (2H, br), 1.7 (1H, br), 1.42(3H, br).

Example 443-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)benzonitrile

The title compound was prepared using the procedure described in Example42E substituting 3-cyanophenylboronic acid for 4-cyanophenylboronicacid. The title compound was treated with one equivalent of L-tartaricacid in IPA:ethanol to give the tartrate salt. mp 172° C.; MS (ESI) 342(M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.2 (1H, d), 8.61 (1H, d), 8.42 (2H,overlapping), 8.21 (1H, d), 8.19 (1H, d), 8.17 (1H, dt), 7.82 (1H, dt),7.75 (1H, t), 4.88 (2H, s), 4.06 (1H, m), 3.90 (3H, m), 3.65 (2H, m),2.40 (1H, m), 2.20 (2H, m), 1.84 (1H, m), 1.59 (3H, d).

Example 451-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)phenyl]ethanone

The title compound was prepared using the procedure described in Example42E substituting 3-acetylphenylboronic acid for 4-cyanophenylboronicacid. The title compound was treated with HCl in IPA:ethyl acetate togive the dihydrochloride salt. mp 174-175° C.; MS (ESI) 359 (M+H)⁺; ¹HNMR (CD₃OD) δ 9.14 (1H, d), 8.56, 8.50 (1H, d), 8.4 (2H, m), 8.33, 7.79(1H, t), 8.14 (1H, dd), 8.05 (1H, dt), 7.74, 7.52 (1H, dt), 7.627.50(1H, t), 4.02 (1H, m), 3.83 (2H, m), 3.60 (2H, m), 3.41 (1H, m), 2.62(1H, m), 2.37 (1H, m), 2.15 (3H, m), 1.80 (1H, m), 1.53 (3H, s), 1.1(3H, d).

Example 466-(4-methoxyphenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example42E substituting 4-methoxyphenylboronic acid for 4-cyanophenylboronicacid. The title compound was treated with HCl in IPA:ethyl acetate togive the dihydrochloride salt. mp 165° C. (dec.); MS (ESI) 347 (M+H)⁺;¹H NMR (CD₃OD) δ 9.12 (1H, d), 8.46 (2H, m), 8.36 (1H, d), 8.11 (1H, d),7.80 (2H, d), 7.10 (2H, d), 4.02 (1H, m), 3.90 (3H, s), 3.82 (2H, m),3.62 (2H, m), 3.41 (1H, m), 2.39 (2H, m), 2.18 (2H, m), 1.82 (1H, m),1.56 (3H, d).

Example 472-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-[4-(trifluoromethyl)phenyl]quinoline

The title compound was prepared using the procedure described in Example42E substituting 4-(trifluoromethyl)phenylboronic acid for4-cyanophenylboronic acid. The title compound was treated with HCl inIPA:ethyl acetate to give the dihydrochloride salt. mp 143-145° C.(dec.); MS (ESI) 385 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.65 (1H, d), 8.50(1H,$), 8.23 (2H, m), 8.09 (2H, d), 7.91 (2H, d), 7.74 (1H, d), 4.0-3.4(6H, br, m), 3.22 (1H, br), 2.22 (1H, br), 2.0 (2H, m), 1.70 (1H, m),1.44 (3H, br).

Example 482-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-[4-(methylsulfonyl)phenyl]quinoline

The title compound was prepared using the procedure described in Example42E substituting 4-(methylsulfonyl)phenylboronic acid for4-cyanophenylboronic acid. The title compound was treated with HCl inIPA:ethyl acetate to give the dihydrochloride salt. MS (ESI) 395 (M+H)⁺;¹H NMR (CD₃OD) δ 9.05 (1H, d), 8.56 (1H, d), 8.45 (1H, dd), 8.38 (1H,d), 8.10 (4H, m), 8.02 (1H, d), 4.03 (1H, br, m), 3.85 (1H, br, m), 3.75(2H, br, m), 3.62 (2H, br, m), 3.41 (1H, m), 3.18 (3H, s), 2.39 (1H, m),2.18 (2H, m), 1.82 (1H, m), 1.57 (3H, br, d).

Example 496-(3,5-difluorophenyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example42E substituting 3,5-difluorophenylboronic acid for 4-cyanophenylboronicacid. The title compound was treated with HCl in IPA:ethyl acetate togive the dihydrochloride salt. mp 164-165° C.; MS (ESI) 353 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 8.72 (1H, d), 8.59 (1H, s), 8.31 (2H, m), 7.76 (1H, d),7.63 (2H, dd), 7.55 (1H, tt). 3.90 (1H, br), 3.63 (2H, br, m), 3.50 (2H,br, m), 3.23 (1H, br), 2.9-2.6 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br,m), 1.64 (1H, br, m), 1.45 (3H, br).

Example 50(3-fluorophenyl)(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinolinyl)methanone

The product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) wastreated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at −78° C. Thesolution was mixed for 15 min, and treated with a solution of3-fluoro-N-methoxy-N-methylbenzamide (2.0 mmol) in THF (5.0 mL) at −78°C. The mixture was allowed to warm to room temperature overnight,quenched by 1 mL ethanol, concentrated, and diluted with ethyl acetate.The mixture was washed with 5% NaHCO₃ (25 mL×3), 25% brine (25 mL),dried over Na₂SO₄, filtered, and the filtrate was concentrated todryness. The residue was purified by column chromatography(heptane:acetone:CH₂Cl₂:TEA (60:40:5:1) to provide the title compound.The title compound was treated with HCl in IPA:ethyl acetate to give thedihydrochloride salt. mp 162-164° C. (dec.); MS (ESI) 363 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 8.79 (1H, d), 8.53 (1H, d), 8.30 (1H, d), 8.21 (1H, dd),7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H,br, m), 3.21 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br, m), 1.7 (1H, br,m), 1.46 (1H, m), 1.30 (3H, d).

Example 512-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-(3-pyridinyl)quinoline

Tetrakis(triphenylphosphine)palladium(0) (28.8 mg, 0.025 mmol),2-(dicyclohexylphosphino)biphenyl (35.0 mg, 0.10 mmol),3-pyridinylboronic acid (0.375 mmol), and sodium carbonate (40.0 mg,0.375 mmol) were combined in 1,2-dimethoxyethane (4 mL) and water (1.5mL). The mixture was then treated with the product from Example 42D (80mg, 0.25 mmol) and heated at 80° C. for 24 hours. The reaction mixturewas allowed to cool to room temperature and diluted with ethyl acetate(20 mL). The organic layer was separated, washed with 5% NaHCO₃ (25mL×3), 25% brine (25 mL), dried over Na₂SO₄, filtered, and the filtratewas concentrated to dryness. The residue was purified by columnchromatography (heptane:acetone:CH₂Cl₂:TEA (60:40:5:1) to provide thetitle compound. The title compound was treated with HCl in IPA:ethylacetate to give the trihydrochloride salt. mp 205-207° C.; MS (ESI) 318(M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.48 (1H, br, s), 9.05 (1H, d), 8.96 (1H, d),9.00 (1H, d), 8.86 (1H, br, s), 8.60 (1H, d), 8.59 (1H, d), 8.32 (1H,dd), 8.23 (1H, d), 4.08 (1H, br, m), 3.90 (2H, br, m), 3.65 (2H, br, m),3.46 (1H, q), 2.40 (1H, m), 2.19 (2H, m), 1.84 (1H, m), 1.58 (3H, d).

Example 524-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrileExample 52A ethyl (6-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate

n-Butyllithium (14 mL, 2 M in pentane) was added dropwise to a solutionof diisopropylamine (2.86 g, 28 mmol) in tetrahydrofuran (60 mL) cooledto −70° C. After 30 minutes of stirring at −70° C., the mixture wastreated with 6-bromo-1-indanone (4.8 g, 22.7 mmol), prepared accordingto the procedure described in J. Org. Chem., 49:4226-423 (1984), in twoportions over 5 minutes. After 10 minutes, the mixture was allowed towarm to −50° C. and was treated with ethyl bromoacetate (4.8 g, 28mmol). The mixture was allowed to warm to −10° C. and was stirred at −10to −15° C. for 1 hour. The reaction was quenched by careful addition ofwater (60 mL) followed by isopropyl acetate (60 mL). The organic layerwas separated, washed with aqueous HCl (50 mL, prepared by adjusting thepH of water to 2 with conc. HCl), and then aqueous potassium carbonate(50 mL, 5%). The organic layer was concentrated under vacuum to providethe title compound which was used in the next step without furtherpurification.

Example 52B (6-bromo-1-hydroxy-2,3-dihydro-1H-inden-2-yl)acetic acid

The product from Example 52A in THF was treated withtert-butylaminoborane (1.18 g, 13.5 mmol) and heated at 40-45° C. for2.5 hours. The mixture was treated with sodium hydroxide solution (1.8 gin water, 40 mL) and heating was continued for 30 minutes. The mixturewas allowed to cool to room temperature and the aqueous layer wasseparated. The organic layer was diluted with isopropyl acetate (40 mL)and water (40 mL) and combined with the aqueous layer. The solution wascooled to 0° C. and the pH was adjusted to 2 by addition of concentratedhydrochloric acid. The mixture was filtered and the filter cake dried atroom temperature. The solid was slurried in dichloromethane (6 mL),refiltered, and redried to provide the title compound.

Example 52C methyl (5-bromo-1H-inden-2-yl)acetate

The product from Example 52B (1.35 g, 5 mmol) in methanol (12 mL) wastreated with concentrated sulfuric acid (2 mL) and heated to gentlereflux. After 2 hours, additional sulfuric acid was added (1 mL) andheating was continued for another 2 hours. The mixture was concentratedunder vacuum and the residue was diluted with water (15 mL). The mixturewas cooled to 10° C., filtered, and the filter cake washed with water (5mL) and dried to provide the title compound. ¹H NMR (CDCl₃) δ 3.42 (s,2H); 3.55 (s, 2H); 3.74 (s, 3H); 6.65 (m, 1H); 7.22-7.31 (m, 2H), 7.44(m, 1H).

Example 52D 2-(5-bromo-1H-inden-2-yl)ethanol

The product from Example 52C (1.1 g, 4.1 mmol) in diethyl ether (5 mL)was added dropwise to a suspension of lithium aluminum hydride (0.125 g,3.3 mmol) in diethyl ether (10 mL) maintaining the internal temperaturebelow 10° C. After stirring for 30 minutes, the reaction mixture wasdiluted with diethyl ether (10 mL), cooled to 0° C., and treated withsaturated aqueous sodium sulfate dropwise. The ethereal solution wasdecanted, dried with sodium sulfate, filtered, and the filtrate wasconcentrated to provide the title compound which was used withoutfurther purification in the next step. ¹H NMR (CDCl₃) δ 2.77 (m, 2H);3.32 (s, 2H); 3.88 (t, J=6.5 Hz, 2H); 6.56 (m, 1H), 7.23 (m, 2H); 7.40(m, 1H).

Example 52E 2-(7-bromo-3-isoquinolinyl)ethanol

The product from Example 52D (0.85 g, 3.5 mmol) in methanol (15 mL) at−70° C. was ozonated until a bluish color developed (˜10 minutes). Themixture was treated with dimethylsulfide (0.7 mL, excess) and sodiumbicarbonate (0.2 g) and allowed to warm to room temperature. Afterstirring for 3 hours, the mixture was treated with aqueous ammoniumhydroxide (7.4 mL, 28%). After stirring an additional 4 hours, thereaction mixture was concentrated under vacuum and then diluted withdichloromethane (20 mL). The organic layer was separated and evaporatedto provide the title compound which was used without furtherpurification in the next step. ¹H NMR (CDCl₃) δ 3.13 (t, J=5.6 Hz, 2H);4.07 (t, J=5.6 Hz, 2H); 7.47 (s, 1H); 7.61 (d, J=8.7 Hz, 1H); 7.71 (dd,J=1.9, 8.7 Hz, 1H); 9.04 (s, 1H); Anal. Calcd. for C₁₁H₁₀BrNO: C, 52.41;H, 4.00; N, 5.56. Found: C, 52.51; H, 3.94; N, 5.42.

Example 52F 2-(7-bromo-3-isoquinolinyl)ethyl 4-methyl benzenesulfonate

The product from Example 52E (0.51 g, 2.0 mmol), tosyl chloride (0.68 g,3.6 mmol), triethylamine (0.55 g, 5.4 mmol), and DMAP (25 mg, 0.2 mmol)were combined in dichloromethane (20 mL) and stirred at room temperaturefor 6 hours. The mixture was treated with water (0.5 mL), stirred for 2hours, and then treated with additional water (15 mL). The organic layerwas separated, washed with aqueous sodium chloride solution (10 mL,10%), evaporated in vacuo, and the residue was azeotroped with heptane(15 mL) to provide the title compound which was used in the next stepwithout further purification.

Example 52G7-bromo-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

The product from Example 52F was dissolved in a solution of(2R)-2-methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). Thesolution was treated with potassium carbonate (0.5 g, 3.6 mmol) andheated at 50-55° C. for 20 hours in a sealed flask. The mixture wasallowed to cool to room temperature, filtered, and the filtrate wasconcentrated in vacuo. The residue was diluted with MTBE (20 mL) andwater (20 mL) and the pH was adjusted to 3-3.5 with concentrated HCl.The aqueous layer was separated, extracted with MTBE (10 mL), adjustedto a pH of 8-8.5 with potassium carbonate, and extracted with isopropylacetate (20 mL). The organic layer was separated and concentrated invacuo. The residue was dissolved in heptane (20 mL), filtered, and thefiltrate concentrated under vacuum to provide the title compound. ¹H NMR(CDCl₃) δ 1.10 (d, J=6.1 Hz, 3H); 1.35-1.49 (m, 1H); 1.62-1.85 (m, 2H);1.85-1.98 (m, 1H); 2.23 (q, J=8.8. Hz, 1H); 2.28-2.42 (m, 1H); 2.46-2.57(m, 1H), 3.04-3.19 (m, 2H); 3.19-3.30 (m, 2H); 7.47 (s, 1H); 7.60 (d,J=8.8 Hz, 1H), 7.64-7.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMSCalcd. for [C₁₆H₁₉BrN₂+H⁺]: 319.0810. Found: 319.0795.

Example 52H4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile

The product from Example 52G (0.2 g, 0.6 mmol), 4-cyanophenylboronicacid (0.22 g, 1.5 mmol), bis(triphenylphosphine)palladium dichloride (55mg, 0.08 mmol), and potassium phosphate (7 mL, 0.2 M in water) werecombined in isopropanol (7 mL) and heated at 60-65° C. for 7 hours in asealed flask. The mixture was filtered through diatomaceous earth, thefiltrate was concentrated in vacuo, and then partitioned between MTBE(10 mL) and water (10 mL). The organic layer was separated, washed withaqueous sodium bicarbonate solution (5%, 10 mL), and then extracted witha solution of 2M HCl (15 mL). The pH of the acidic aqueous layer wasadjusted with base using potassium carbonate and extracted withisopropyl acetate (15 mL). The organic layer was evaporated in vacuo andthe residue was chased with heptane (10 mL) to provide the titlecompound. ¹H NMR (CDCl₃) δ 1.12 (d, J=6.0 Hz, 3H); 1.37-1.50 (m, 1H);1.64-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.26 (q, J=8.8. Hz, 1H); 2.32-2.43(m, 1H); 2.50-2.60 (m, 1H), 3.09-3.34 (m, 4H); 7.56 (m, 1H); 7.73-7.81(m, 4H), 7.84-7.87 (m, 2H), 8.12 (m, 1H); 9.26 (s, 1H); HRMS Calcd. for[C₂₃H₂₃N₃+H⁺]: 342.1970. Found: 342.1974.

Example 533-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile

The title compound was prepared using the procedure described in Example52H substituting 3-cyanophenylboronic acid for 4-cyanophenylboronicacid. ¹H NMR (CDCl₃) δ 1.15 (d, J=6.1 Hz, 3H); 1.39-1.54 (m, 1H);1.66-1.87 (m, 2H); 1.88-2.01 (m, 1H); 2.29 (q, J=8.8. Hz, 1H); 2.34-2.47(m, 1H); 2.52-2.65 (m, 1H), 3.09-3.40 (m, 4H); 7.58 (m, 1H); 7.61 (d,J=7.8 Hz, 1H); 7.64-7.70 (m, 1H), 7.82-7.89 (m, 2H); 7.89-7.95 (m, 1H);7.97 (m, 1H), 8.10 (m, 1H); 9.27 (s, 1H).

Example 546-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinolineExample 54A (2R)-2-methyl-1-[2-(4-nitrophenyl)ethyl]pyrrolidine

(2R)-2-Methylpyrrolidine L-tartrate (4.0 g, 17.0 mmol),1-(2-bromoethyl)-4-nitrobenzene (9.8 g, 43 mmol), and potassiumcarbonate (12 g, 85 mmol), were combined in DMF (20 mL) in a sealed tubeat 50° C. and stirred vigorously for 16 hours. The mixture was allowedto cool to room temperature, diluted with diethyl ether (100 mL), washedwith water (2 times, 100 mL and then 50 mL), and extracted with 1M HCl(2 times, 50 mL and 25 mL). The aqueous acidic extractions werecombined, washed with diethyl ether (50 mL), cooled to 0° C., adjustedto pH 14 with 50% NaOH solution, and extracted with dichloromethane (3times, 50 mL). The dichloromethane extractions were combined, dried(MgSO₄), filtered, and the filtrate concentrated to provide the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 1.08 (d, J=6 Hz, 3 H), 1.43 (m, 1H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H), 2.34 (m, 2 H),2.91 (m, 2 H), 3.03 (m, 1 H), 3.22 (td, J=8, 3 Hz, 1 H), 7.38 (d, J=9Hz, 2 H), 8.15 (d, J=9 Hz, 2 H); MS (DCI/NH₃) m/z 235 (M+H)⁺.

Example 54B 4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}aniline

The product from Example 54A (3.85 g, 16.4 mmol) was hydrogenated using10% Pd/C (0.39 g) in methanol (20 mL) under 1 atm H₂ for 16 hours. Afterthe H₂ was replaced with N₂, the mixture was diluted with methanol (150mL), stirred for 15 minutes, filtered, and the filtrate was concentratedto provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.11 (d, J=6Hz, 3 H), 1.43 (m, 1 H), 1.74 (m, 2 H), 1.90 (m, 1 H), 2.25 (m, 3 H),2.70 (m, 2 H), 2.97 (m, 1 H), 3.24 (td, J=9, 3 Hz, 1 H), 3.55 (s, 2 H),6.63 (d, J=8 Hz, 2 H), 7.01 (d, J=8 Hz, 2 H); MS (DCI/NH₃) m/z 205(M+H)⁺.

Example 54C2,2-dimethyl-N-(4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)propanamide

The product from Example 54B (2.77 g, 14 mmol) was dissolved inanhydrous dichloromethane (70 mL) under nitrogen, treated withtriethylamine (2.3 mL, 16 mmol), cooled to 0° C., treated withtrimethylacetyl chloride (1.9 mL, 15 mmol), stirred at ambienttemperature for 60 hours and treated with 1M NaOH (40 mL). The layerswere separated and the aqueous layer was extracted with dichloromethane(2 times, 40 mL). The combined dichloromethane layers were dried(MgSO₄), filtered, and the filtrate was concentrated to provide 4.0 g ofthe title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.10 (d, J=6 Hz, 3 H),1.31 (s, 9 H), 1.44 (m, 1 H), 1.76 (m, 2 H), 1.92 (m, 1 H), 2.18 (q, J=9Hz, 1 H), 2.27 (m, 2 H), 2.78 (m, 2 H), 2.99 (m, 1 H), 3.23 (td, J=9, 3Hz, 1 H), 7.17 (d, J=8 Hz, 2 H), 7.44 (d, J=8 Hz, 2 H); MS (DCI/NH₃) m/z289 (M+H)⁺.

Example 54DN-(2-formyl-4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)-2,2-dimethylpropanamide

The product from Example 54C (4.0 g, 13.9 mmol) under nitrogen inanhydrous diethyl ether (140 mL) was treated withN,N,N′N′-tetramethylethylenediamine (6.5 mL, 43 mmol), cooled to −5° C.,treated with n-butyllithium (16.7 mL of a 2.5 M solution in hexanes)over 10 minutes, stirred for 4 hours at ambient temperature, cooled to−5° C., treated all at once with anhydrous N,N-dimethylformamide (6.5mL, 83 mmol), stirred for 16 hours at ambient temperature, diluted withdiethyl ether (100 mL), washed with water (75 mL), washed with brine,dried (MgSO₄), filtered, and the filtrate was concentrated. The residuewas purified by chromatography on silica gel eluting with a gradient of2%, 3.5%, 5%, and 7.5% (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.10 (d, J=6 Hz, 3H), 1.35 (s, 9 H), 1.44 (m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q,J=9 Hz, 1 H), 2.31 (m, 2 H), 2.85 (m, 2 H), 3.01 (m, 1 H), 3.23 (td,J=8, 3 Hz, 1 H), 7.47 (dd, J=8, 2 Hz, 1 H), 7.51 (d, J=2 Hz, 1 H), 8.71(d, J=8 Hz, 1 H), 9.92 (s, 1 H), 11.31 (s, 1 H); MS (DCI/NH₃) m/z 317(M+H)⁺.

Example 54E2-amino-5-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}benzaldehyde

The product from Example 54D (2.46 g, 7.8 mmol) in 3M HCl (40 mL) washeated at 80° C. for 4 hours, allowed to cool to room temperature, andcarefully poured into a mixture of 1M NaOH (250 mL) and dichloromethane(75 mL). The layers were separated and the aqueous layer was extractedwith dichloromethane (2 times, 75 mL). The combined dichloromethanelayers were dried (MgSO₄), filtered, and the filtrate was concentrated.The residue was purified by chromatography on silica gel eluting with agradient of 2%, 3.5% and 5% (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.12 (d, J=6 Hz, 3H), 1.50 (m, 1 H), 1.76 (m, 2 H), 1.93 (m, 1H), 2.25 (m, 3 H), 2.76 (m,2 H), 2.99 (m, 1 H), 3.25 (td, J=9, 3 Hz, 1 H), 5.99 (s, 2 H), 6.60 (d,J=8 Hz, 1 H), 7.19 (dd, J=8, 2 Hz, 1 H), 7.31 (d, J=2 Hz, 1 H), 9.85 (s,1 H); MS (DCI/NH₃) m/z 233 (M+H)⁺.

Example 54F6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinoline

The product from Example 54E (32.5 mg, 0.14 mmol) and 3-acetylpyridine(17 mg, 0.14 mmol) were combined in ethanol (2 mL) and treated with onedrop of a saturated solution of potassium hydroxide in ethanol andheated at 80° C. for 16 hours. The mixture was allowed to cool to roomtemperature and concentrated.

The residue was purified by chromatography on silica gel eluting with agradient 10:1:1 to 6:1:1 to 4:1:1 ethyl acetate:formic acid:water. Thefractions containing the product were collected, concentrated, and theresidue repurified by chromatography on silica gel eluting with agradient of 2%, 3.5% and 5% (9:1 MeOH:conc NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.17 (d, J=6 Hz, 3H), 1.47 (m, 1 H), 1.82 (m, 2 H), 2.02 (m, 1 H), 2.35 (q, J=9 Hz, 1 H),2.47 (m, 2 H), 3.04 (m, 2 H), 3.19 (m, 2 H), 7.62 (dd, J=8, 5 Hz, 1 H),7.72 (dd, J=9, 2 Hz, 1 H), 7.82 (d, J=2 Hz, 1 H), 8.04 (d, J=9 Hz, 1 H),8.08 (d, J=9 Hz, 1 H), 8.40 (d, J=9 Hz, 1 H), 8.60 (dt, J=8, 2 Hz, 1 H),8.64 (dd, J=5, 1 Hz, 1 H), 9.32 (d, J=1 Hz, 1 H); MS (DCI/NH₃) m/z 318(M+H)⁺.

Example 556-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-pyridinyl)quinoline

The title compound was prepared using the procedure described in Example54F substituting 4-acetylpyridine acid for 3-acetylpyridine. ¹H NMR (300MHz, CDCl₃) δ 1.14 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.78 (m, 2 H), 1.96(m, 1 H), 2.25 (q, J=9 Hz, 1 H), 2.42 (m, 2 H), 3.09 (m, 3 H), 3.30 (td,J=9, 3 Hz, 1 H), 7.66 (m, 2 H), 7.89 (d, J=9 Hz, 1 H), 8.05 (dd, J=4, 2Hz, 2 H), 8.12 (d, J=9 Hz, 1 H), 8.23 (dd, J=9, 1 Hz, 1 H), 8.78 (dd,J=4, 2 Hz, 2 H); MS (DCI/NH₃) m/z 318 (M+H)⁺.

Example 566-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyridinyl)quinoline

The title compound was prepared using the procedure described in Example54F substituting 2-acetylpyridine acid for 3-acetylpyridine. ¹H NMR (300MHz, CDCl₃) δ 1.14 (d, J=6 Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H), 1.94(m, 1 H), 2.25 (q, J=9 Hz, 1 H), 2.40 (m, 2 H), 3.03 (m, 2 H), 3.14 (m,1 H), 3.30 (td, J=9, 3 Hz, 1 H), 7.35 (ddd, J=8, 5, 1 Hz, 1 H), 7.62(dd, J=9, 2 Hz, 1 H), 7.67 (d, J=1 Hz, 1 H), 7.86 (td, J=8, 2 Hz, 1 H),8.10 (d, J=9 Hz, 1 H), 8.22 (d, J=9 Hz, 1 H), 8.53 (d, J=9 Hz, 1 H),8.63 (d, J=8 Hz, 1 H), 8.73 (m, 1 H); MS (DCI/NH₃) m/z 318 (M+H)⁺.

Example 576-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1,3-thiazol-2-yl)quinoline

The product from Example 54E (46 mg, 0.20 mmol) and1-(1,3-thiazol-2-yl)ethanone (52 mg, 0.41 mmol) were combined in ethanol0.4 mL and treated with one drop of a saturated solution of potassiumhydroxide in ethanol and heated at 80° C. for 16 hours. The mixture wasallowed to cool to room temperature and concentrated. The residue waspurified by chromatography on silica gel eluting with a gradient of 2%and 3.5% (9:1 MeOH:conc NH₄OH) in dichloromethane to provide the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6 Hz, 3 H), 1.46 (m, 1H), 1.77 (m, 2 H), 1.93 (m, 1 H), 2.24 (q, J=9 Hz, 1 H), 2.39 (m, 2 H),3.01 (m, 2 H), 3.11 (m, 1 H), 3.29 (td, J=9, 3 Hz, 1 H), 7.48 (d, J=3Hz, 1 H), 7.63 (m, 2 H), 7.97 (d, J=3 Hz, 1 H), 8.06 (d, J=9 Hz, 1 H),8.19 (d, J=9 Hz, 1 H), 8.31 (d, J=9 Hz, 1 H); (DCI/NH₃) m/z 324 (M+H)⁺.

Example 582-(2,4-dimethyl-1,3-thiazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanone for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6 Hz,3 H), 1.48 (m, 1 H), 1.76 (m, 2 H), 1.94 (m, 1 H), 2.24 (q, J=9 Hz, 1H), 2.39 (m, 2 H), 2.72 (s, 3 H), 2.75 (s, 3 H), 3.01 (m, 2 H), 3.12 (m,1 H), 3.29 (td, J=9, 2 Hz, 1 H), 7.62 (m, 3 H), 7.99 (d, J=9 Hz, 1 H),8.11 (d, J=9 Hz, 1 H); (DCI/NH₃) m/z 352 (M+H)⁺.

Example 596-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyrazinyl)quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-(2-pyrazinyl)ethanone for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.14 (d, J=6 Hz,3 H), 1.46 (m, 1 H), 1.78 (m, 2 H), 1.94 (m, 1 H), 2.25 (q, J=9 Hz, 1H), 2.40 (m, 2 H), 3.05 (m, 2 H), 3.16 (m, 1 H), 3.30 (td, J=9, 3 Hz, 1H), 7.65 (dd, J=8, 2 Hz, 1 H), 7.68 (br. s., 1 H). 8.13 (d, J=8 Hz, 1H), 8.24 (d, J=8 Hz, 1 H), 8.46 (d, J=9 Hz, 1 H), 8.63 (d, J=2 Hz, 1 H),8.66 (dd, J=3, 2 Hz, 1 H), 9.86 (d, J=1 Hz, 1 H); (DCI/NH₃) m/z 319(M+H)⁺.

Example 601-[6-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-pyridinyl]ethanone

The title compound was prepared using the procedure described in Example57 substituting 2,6-diacetylpyridine for 1-(1,3-thiazol-2-yl)ethanone.¹H NMR (300 MHz, CDCl₃) δ 1.14 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.78 (m,2 H), 1.95 (m, 1 H), 2.26 (q, J=9 Hz, 1 H), 2.41 (m, 2 H), 2.88 (s, 3H), 3.04 (m, 2 H), 3.17 (m, 1 H), 3.31 (td, J=9, 3 Hz, 1 H), 7.64 (dd,J=9, 2 Hz, 1 H), 7.69 (d, J=2 Hz, 1 H), 8.00 (t, J=8 Hz, 1 H), 8.10 (m,2 H), 8.25 (d, J=9 Hz, 1 H), 8.66 (d, J=9 Hz, 1 H), 8.88 (dd, J=8, 1 Hz,1 H); (DCI/NH₃) m/z 360 (M+H)⁺.

Example 61 4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrile and4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrile Example 61A 4-bromo-1,2-benzenediamine

4-Bromo-2-nitroaniline (10 g, 46 mmol) in THF (120 mL) was treated with1% Pt/C (1.0 g) and hydrogenated at room temperature under 40 psi of H₂pressure. After 2 hours, the reaction was filtered and the filtrateconcentrated to provide the title compound which was used withoutfurther purification in the next step. MS 188 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ 6.77-6.81 (m, 2H), 6.54 (d, J=8.4 Hz, 1H), 3.28 (br, 4H).

Example 61B 7-bromo-2-methylquinoxaline and 6-bromo-2-methylquinoxaline

The product from Example 61A (9.4 g, 50 mmol) in acetonitrile (100 mL)was treated with 40% aqueous pyruvic aldehyde (11.0 mL, 60 mmol)dropwise. After stirring at room temperature for 2 hours, the mixturewas concentrated and the residue was suspended in IPAc (100 mL) andfiltered. The filtrate was washed with 20% brine, dried with Na₂SO₄,filtered, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography eluting with heptane:EtOH:MeOH (8:2:1)to provide the title compounds. MS 224 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ8.73 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.1 Hz,1H), 7.75-7.93 (m, 4H), 2.78 (s, 3H), 2.76 (s, 3H); ¹³C NMR (400 MHz,CDCl₃) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141.17, 140.45, 139.34,133.17, 132.15, 131.15, 130.75, 130.16, 129.71, 123.66, 122.38, 22.89.

Example 61C 4-(2-methyl-6-quinoxalinyl)benzonitrile and4-(3-methyl-6-quinoxalinyl)benzonitrile

4-Cyanophenylboronic acid (588 mg, 4.0 mmol), cesium carbonate (2.2 g,7.0 mmol), and cesium fluoride (608 mg, 4.0 mmol) were combined in H₂O(15 mL) and treated with the products from Example 61B (446 mg, 2.0mmol) in toluene (10 mL) and heated at 80° C. for 3 hours. The reactionmixture was allowed to cool to room temperature and filtered through apad of celite. The filtrate was partitioned between IPAc (60 mL) and H₂O(50 mL). The organic layer was separated, washed with 20% brine, driedwith Na₂SO₄, filtered, and the filtrate was concentrated under vacuum toprovide the title compounds which were used in the next step withoutfurther purification. MS 246 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s,1H), 8.69 (s, 1H), 8.02-8.20 (m, 4H), 7.84-7.90 (m, 2H), 7.70-7.76 (m,8H), 2.73 (s, 6H); ¹³C NMR (400 MHz, CDCl₃) δ 154.34, 154.10, 146.47,147.17, 143.80, 142.93, 141.74, 140.62, 140.39, 140.18, 139.16, 132.49,130.16, 129.74, 129.25, 128.71, 128.63, 128.06, 127.77, 127.74, 127.66,127.59, 127.22, 126.73, 118.39, 118.37, 111.61, 111.51, 22.96.

Example 61D4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrileand4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-6-quinoxalinyl)benzonitrile

(2R)-2-Methylpyrrolidine hydrochloride 5 (973 mg, 8.0 mmol) and 37%aqueous solution of formaldehyde (0.57 mL, 7.0 mmol) were combined inEtOH (20 mL) and heated in a sealed tube at 85° C. for 1 hour. Themixture was allowed to cool to room temperature, treated with theproducts from Example 61C (500 mg, 2.0 mmol), and heated at 85° C.overnight. The mixture was allowed to cool to room and concentrated todryness under vacuum. The residue was partitioned between IPAc (50 mL)and 20% brine (40 mL). The organic layer was separated, dried withNa₂SO₄, filtered, and the filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography eluting withheptane:acetone:CH₂Cl₂:Et₃N (60:40:3:1) to provide the title compounds.MS 343 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 7.72 (s, 1H),8.16 (m, 2H), 8.06 (m, 2H), 7.85 (m, 2H), 7.70 (m, 4H), 3.17 (m, 8H),2.52 (m, 2H), 2.31 (m, 2H), 2.17 (m, 2H), 1.83 (m, 2H), 1.65 (m, 4H),1.32 (m, 2H). ¹³C NMR (400 MHz, CDCl₃) δ 156.63, 156.41, 146.45, 145.16,143.73, 143.70, 141.75, 141.53, 140.81, 140.60, 139.89, 139.04, 132.38,129.66, 129.36, 128.42, 127.68, 127.65, 127.55, 137.13, 126.86, 118.29,111.48, 111.40, 59.87, 53.93, 52.89, 35.83, 32.90, 21.98, 19.25.

Example 627-(2,6-difluoro-3-pyridinyl)-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinolineExample 62A methyl 5-bromo-2-iodobenzoate

To a stirred slurry of methyl 2-iodo-benzoate (5.0 g, 0.019 mol) andN-bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was addedconcentrated H₂SO₄ (10 mL) dropwise, keeping the temperature at 20-40°C. The mixture was stirred at room temperature for 88 hours and thenheated at 50° C. for 4 hours. The mixture was cooled to 10° C., treatedwith 40 g of ice water, and extracted with 50 mL of CH₂Cl₂. The organicphase was washed in succession with 2×50 mL 5% NaHCO₃, 50 mL 10%Na₂S₂O₃, 50 mL water, and concentrated to colorless oil. The residue waspurified by column chromatography (silica gel, 10:90 EtOAc:hexane) toprovide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (d, J=4 Hz,1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92 (s, 3H); MS(DCI/NH₃) [M+NH₄]⁺ at 358, [M+NH₃NH₄]⁺ at 375.

Example 62B (5-bromo-2-iodophenyl)methanol

To a stirred mixture of NaBH₄ (11.18 g, 0.296 mol) in EtOH (200 mL) at5° C. was added the product from Example 62A (50.4 g, 0.148 mol) in THF(100 mL). The mixture was allowed to warm to room temperature andstirred for 18 hours. The mixture was treated with additional NaBH₄ (8.4g, 0.222 mol) and was stirred for 22 hours. The mixture was cooled to 0°C., treated with 100 mL of 15% aqueous citric acid slowly, and extractedwith 600 mL of CH₂Cl₂. The organic phase was washed with 200 mL of 15%NaCl and concentrated to provide the title compound. ¹H NMR (CDCl₃, 400MHz) δ 7.64 (d, J=8 Hz, 1H), 7.61 (d, J=4 Hz, 1H), 7.12 (dd, J=4, 8 Hz,1H), 4.63 (d, J=8 Hz, 2H), 1.98 (t, J=8 Hz, 1H). MS (DCI/NH₃) [M+NH₄]⁺at 330, [M+NH₄—H₂O]⁺ at 312.

Example 62C 5-bromo-2-iodobenzaldehyde

A solution of oxalyl chloride (1.53 g, 0.012 mol) in CH₂Cl₂ (15 mL) wascooled to −70° C., and DMSO (1.41 g, 0.018 mol) in CH₂Cl₂ (15 mL) wasadded at −65 to −70° C. The mixture was stirred under nitrogen for 10minutes at −70° C. and then treated with the product from Example 62B(2.35 g, 7.5 mmol) in 60 mL CH₂Cl₂. The slurry was stirred at −65° C.for 15 minutes and treated with triethylamine (3.8 g, 0.037 mol). Themixture was allowed to warm to −10° C. over 1 hour. The mixture wastreated with 20 mL of water and allowed to warm to room temperature. Theorganic layer was separated and concentrated to provide the titlecompound. ¹H NMR (CDCl₃, 400 MHz) δ 9.97 (s, 1H), 7.97 (d, J=4 Hz, 1H),7.79 (d, J=8 Hz, 1H), 7.40 (dd, J=4, 8 Hz, 1H). MS (DCI/NH₃) [M+NH₄]⁺ at328.

Example 62D N-[(1E)-(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine

The product from Example 62C (2.28 g, 7.3 mmol) in THF (10 mL) wastreated with t-butylamine (1.61 g, 22.0 mmol) and stirred under nitrogenat room temperature for 40 hours. The mixture was concentrated underreduced pressure and the residue was dissolved in 30 mL of methylenechloride. The methylene chloride was washed with 10 mL water andconcentrated to provide the title compound which was used in the nextstep without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (s,1H), 8.05 (d, J=4 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.19 (dd, J=4, 8 Hz,1H), 1.34 (s, 9H). MS (DCI/NH₃) 366 [M+H]⁺.

Example 62E 2-(7-bromo-3-isoquinolinyl)ethanol

The product from Example 62D (1.3 g, 3.6 mmol), 3-butyn-1-ol (0.3 g, 4.3mmol), CuI (0.04 g, 0.2 mmol), and PdCl₂(PPh₃)₂ (0.08 g, 0.1 mmol) werecombined in toluene (15 mL). The mixture was treated withdiisopropylamine (0.54 g, 5.3 mmol) and stirred at room temperature for4 hours. The mixture was then treated with additional CuI (0.07 g, 0.4mmol) and heated at 100° C. for 4 hours. The mixture was allowed to coolto room temperature, diluted with 30 mL CH₂Cl₂, and filtered. Thefiltrate was washed with 2×10 mL 15% NaCl and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,10:90 MeOH:CHCl₃) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz)δ 9.08 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.73 (dd, J=8, 4 Hz, 1H), 7.63 (d,J=8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J=4 Hz, 2H), 3.92 (s, 1H), 3.15 (t,J=4 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ 153.8, 150.3, 134.5, 133.8,129.4, 127.6, 120.0, 118.6, 62.3, 39.4. MS (DCI/NH₃) 252, 254 [M+H]⁺.

Example 62F7-bromo-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

The product from Example 62E (0.5 g, 2.0 mmol) and triethylamine (0.5 g,4.9 mmol) were combined in THF (15 mL) at −15° C. The mixture wastreated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at0-10° C. for 2 hours. The mixture was treated with additionalmethanesulfonyl chloride (0.2 mmol) and stirred at room temperature for16 hours. The mixture was treated with (2R)-2-methylpyrrolidinehydrochloride (0.72 g, 6.0 mmol) and K₂CO₃ (0.27 g, 2.0 mmol) inacetonitrile (25 mL) and then the mixture was heated at 60° C. for 20hours. The mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure. The residue was dissolved in 20 mLCH₂Cl₂, washed with 5 mL of water and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,10:90 MeOH:CHCl₃) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz)δ 9.10 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64(d, J=12 Hz, 1H), 7.58 (s, 1H), 3.46-3.40 (m, 2H), 3.34-3.29 (m, 2H),2.91-1.85 (m, 1H), 2.81-2.68 (m, 1H), 2.59-2.49 (m, 1H), 2.11-2.02 (m,1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.32 (d,J=8 Hz, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 152.5, 150.6, 134.5, 133.6,129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32.4, 21.9,17.9. MS (DCI/NH₃) 319, 321 [M+H].

Example 62G7-(2,6-difluoro-3-pyridinyl)-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

The product from Example 62F (0.30 g, 0.9 mmol),2,6-difluoro-3-pyridineboronic acid (0.3 g, 1.9 mmol),2-(dicyclohexylphosphino)biphenyl (66 mg, 0.2 mmol), and PdCl₂(PPh₃)₂(66 mg, 0.1 mmol) were combined in isopropanol (15 mL). The mixture wastreated with a solution of Na₂CO₃ (0.15 g, 1.4 mmol, in 5 mL water) andheated at 65° C. for 16 hours. After cooling to room temperature, themixture was diluted with 20 mL of CH₂Cl₂ and filtered. The filtrate waswashed with 10 mL of 15% NaCl and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 10:90:1MeOH:CHCl₃:Et₃N) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz)δ 9.25 (s, 1H), 8.11-8.05 (m, 2H), 7.85 (d, J=10 Hz, 1H), 7.81-7.78 (m,1H), 7.58 (s, 1H), 6.98 (dd, J=10 Hz, 1H), 3.34-3.27 (m, 2H), 3.22-3.15(m, 2H), 2.65-2.56 (m, 1H), 2.45-2.40 (m, 1H), 2.33-2.27 (m, 1H),2.01-1.91 (m, 1H), 1.87-1.80 (m, 1H), 1.77-1.70 (m, 1H), 1.52-1.42 (m,1H), 1.16 (d, J=8 Hz, 3H); ¹³C NMR (CDCl₃, 400 MHz) δ 158.9, 154.6,151.9, 144.6, 144.5, 135.6, 130.7, 130.2, 127.3, 126.7, 126.6, 118.1,1006.8, 106.5, 60.2, 54.2, 54.1, 37.5, 32.9, 22.0, 19.2.

Example 633-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-(3-pyridinyl)isoquinolineExample 63A 2-[7-(3-pyridinyl)-3-isoquinolinyl]ethanol

The product from Example 62E (0.3 g, 1.2 mmol), 3-pyridineboronic acid(0.22 g, 1.8 mmol), 2-(dicyclohexylphosphino)biphenyl (80 mg, 0.2 mmol),and PdCl₂(PPh₃)₂ (80 mg, 0.1 mmol) were combined in isopropanol (15 mL)and treated with a solution of Na₂CO₃ (0.19 g, 1.8 mmol) in water (5 mL)and heated at 65° C. for 16 hours. After cooling to room temperature,the mixture was diluted with 20 mL of CH₂Cl₂ and filtered. The filtratewas washed with 10 ml 15% NaCl and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 10:90MeOH:CHCl₃) to provide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ9.24 (s, 1H), 8.95 (d, J=4 Hz, 1H), 8.65 (dd, J=2, 8 Hz, 1H), 8.13 (bs,1H), 7.98 (2 m, 1H), 7.91-7.86 (m, 2H), 7.55 (s, 1H), 7.44-7.41 (2d,1H), 4.11 (t, J=4 Hz, 2H), 3.19 (t, J=4 Hz, 2H); ¹³C NMR (CDCl₃, 400MHz) δ 153.9, 151.7, 148.6, 148.0, 135.9, 135.5, 135.4, 134.2, 129.5,127.2, 126.9, 125.4, 123.5, 118.5, 62.4, 39.4.

Example 63B3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-(3-pyridinyl)isoquinoline

The product from Example 63A (0.25 g, 1.0 mmol) and triethylamine (0.15g, 1.5 mmol) in methylene chloride (10 mL) at −5° C. were treated withmethanesulfonyl chloride (0.12 g, 1.2 mmol) and stirred at 0° C. for 2hours and then stirred at room temperature for 15 hours. The mixture wasconcentrated under reduced pressure and the residue was treated withK₂CO₃ (0.21 g, 1.5 mmol) and (2R)-2-methylpyrrolidine (0.13 g, 1.5 mmol)in acetonitrile (15 mL), and then heated at 60° C. for 5 hours. Themixture was concentrated under reduced pressure and the residue wasdissolved in 30 mL methylene chloride, washed with 10 mL 15% NaCl, andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 10:90:1 MeOH:CHCl₃:Et₃N) to provide thetitle compound. ¹H NMR (CDCl₃, 400 MHz) δ 9.27 (s, 1H), 8.95 (m, 1H),8.64 (dd, J=2, 4 Hz, 1H), 8.12 (s, 1H), 7.98 (m, 1H), 1.90-1.86 (m, 2H),7.56 (s, 1H), 7.44-7.40 (m, 1H), 3.37-3.28 (m, 2H), 3.26-3.18 (m, 2H),2.68-2.61 (m, 2H), 2.51-2.46 (m, 1H), 2.38-2.31 (m, 1H), 2.00-1.93 (m,1H), 1.88-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.55-1.46 (m, 1H), 1.14 (d,3H); ¹³C NMR (CDCl₃, 400 MHz) δ 9.27 153.8, 151.9, 148.4, 147.9, 135.6,135.5, 135.4, 134.1, 129.1, 127.0, 126.9, 125.2, 123.4, 118.2, 60.4,54.1, 54.0, 37.2, 32.8, 21.9, 19.0.

Example 643-(benzyloxy)-2-methyl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-(benzyloxy)acetone for 1-(1,3-thiazol-2-yl)ethanone.¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6.1 Hz, 3 H), 1.46 (m, 1 H), 1.75(m, 1 H), 1.94 (m, 1 H), 2.23 (q, J=8.8 Hz, 1 H), 2.37 (m, 2 H), 2.70(s, 3 H), 2.97 (m, 2 H), 3.11 (m, 1 H), 3.28 (m, 1 H), 5.20 (s, 2 H),7.31 (s, 1 H), 7.35-7.46 (m, 5 H), 7.50 (m, 3 H), 7.89 (d, J=8.5 Hz, 1H); (DCI/NH₃) m/z 361 (M+H)⁺.

Example 652-cyclopropyl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-cyclopropylethanone for 1-(1,3-thiazol-2-yl)ethanone.¹H NMR (300 MHz, CDCl₃) δ 1.02-1.16 (m, 4 H), 1.12 (d, J=6.1 Hz, 3 H),1.45 (m, 1 H), 1.76 (m, 2 H), 1.93 (m, 1 H), 2.23 (m, 2 H), 2.37 (m, 2H), 2.98 (m, 2 H), 3.10 (m, 1 H), 3.28 (m, 1 H), 7.13 (d, J=8.5 Hz, 1H), 7.50-7.56 (m, 2 H), 7.88 (d, J=8.5 Hz, 1 H), 7.93 (d, J=8.5 Hz, 1H); (DCI/NH₃) m/z 281 (M+H)⁺.

Example 664-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)benzonitrile

The title compound was prepared using the procedure described in Example57 substituting 4-acetylbenzonitrile for 1-(1,3-thiazol-2-yl)ethanone.¹H NMR (400 MHz, CDCl₃) δ 1.13 (d, J=5.8 Hz, 3 H), 1.46 (m, 1 H), 1.73(m, 1 H), 1.83 (m, 1 H), 1.95 (m, 1 H), 2.25 (q, J=8.6 Hz, 1 H), 2.40(m, 2 H), 3.03 (m, 2 H), 3.14 (m, 1 H), 3.29 (dt, J=8.4, 2.3 Hz, 1 H),7.66 (m, 2 H), 7.81 (d, J=8.6 Hz, 2 H), 7.86 (d, J=8.3 Hz, 1 H), 8.09(d, J=8.6 Hz, 1 H), 8.22 (d, J=8.29 Hz, 1 H), 8.29 (d, J=8.59 Hz, 2 H);(DCI/NH₃) m/z 342 (M+H)⁺.

Example 672,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)nicotinonitrile

The title compound was prepared using the procedure described in Example57 substituting 5-acetyl-2,6-dimethylnicotinonitrile for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.14 (d, J=6.10Hz, 3 H), 1.48 (m, 1 H), 1.77 (m, 2 H), 1.95 (m, 1 H), 2.25 (q, J=8.70Hz, 1 H), 2.40 (m, 2 H), 2.69 (s, 3 H), 2.82 (s, 3 H), 3.10 (m, 3 H),3.30 (m, 1 H), 7.50 (d, J=8.48 Hz, 1 H), 7.68 (dd, J=2.03, 8.48 Hz, 1H), 7.71 (bs, 1 H), 8.06 (d, J=8.48 Hz, 1 H), 8.06 (s, 1 H), 8.22 (d,J=8.48 Hz, 1 H); (DCI/NH₃) m/z 371 (M+H)⁺.

Example 682-(3-methyl-2-pyrazinyl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-(3-methyl-2-pyrazinyl)ethanone for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.14 (d, J=6.10Hz, 3 H), 1.47 (m, 1 H), 1.77 (m, 2 H), 1.95 (m, 1 H), 2.25 (q, J=8.81Hz, 1 H), 2.41 (m, 2 H), 2.94 (s, 3 H), 3.10 (m, 3 H), 3.31 (td, J=8.39,2.54 Hz, 1 H), 7.66 (dd, J=8.65, 1.86 Hz, 1 H), 7.70 (d, J=2.00 Hz, 1H), 8.02 (d, J=8.48 Hz, 1 H), 8.09 (d, J=8.48 Hz, 1 H), 8.25 (d, J=8.82Hz, 1 H), 8.53 (m, 2 H); (DCI/NH₃) m/z 333 (M+H)⁺.

Example 69 ethyl5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-3-isoxazolecarboxylate

The title compound was prepared using the procedure described in Example57 substituting ethyl 5-acetyl-3-isoxazolecarboxylate for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6.10Hz, 3 H), 1.45 (m, 1 H), 1.46 (t, J=7.12 Hz, 3 H), 1.77 (m, 2 H), 1.95(m, 1 H), 2.24 (q, J=8.48 Hz, 1 H), 2.38 (m, 2 H), 2.97-3.22 (m, 3 H),3.29 (m, 1 H), 4.50 (q, J=7.12 Hz, 2 H), 7.46 (s, 1 H), 7.68 (m, 2 H),8.02 (d, J=8.48 Hz, 1 H), 8.09 (d, J=8.82 Hz, 1 H), 8.25 (d, J=8.48 Hz,1 H); (DCI/NH₃) m/z 380 (M+H)⁺.

Example 705-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarbonitrile

The title compound was prepared as the major product using the proceduredescribed in Example 57 substituting 5-acetyl-2-thiophenecarbonitrilefor 1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d,J=5.76 Hz, 3 H), 1.46 (m, 1 H), 1.76 (m, 2 H), 1.95 (m, 1 H), 2.23 (q,J=8.59 Hz, 1 H), 2.40 (m, 2 H), 3.01 (m, 2 H), 3.14 (m, 1 H), 3.28 (dt,1 H), 7.64 (m, 4 H), 7.77 (d, J=8.81 Hz, 1 H), 8.01 (d, J=9.15 Hz, 1 H),8.15 (d, J=9.15 Hz, 1 H); (DCI/NH₃) m/z 348 (M+H)⁺.

Example 71 ethyl5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarboximidoate

The title compound was prepared as a minor product using the proceduredescribed in Example 57 substituting 5-acetyl-2-thiophenecarbonitrilefor 1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d,J=6.10 Hz, 3 H), 1.44 (t, J=7.12 Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H),1.95 (m, 1 H), 2.24 (q, J=8.82 Hz, 1 H), 2.39 (m, 2 H), 3.00 (m, 2 H),3.12 (m, 1 H), 3.29 (m, 1 H), 4.34 (q, J=7.46 Hz, 2 H), 7.60 (m, 4 H),7.77 (d, J=8.48 Hz, 1 H), 8.01 (d, J=9.16 Hz, 1 H), 8.10 (d, J=8.48 Hz,1 H); (DCI/NH₃) m/z 394 (M+H)⁺.

Example 722-(2,4-dimethyl-1,3-oxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

The title compound was prepared using the procedure described in Example57 substituting 1-(2,4-dimethyl-1,3-oxazol-5-yl)ethanone for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.20 (d, J=6.10Hz, 3 H), 1.50 (m, 1 H), 1.85 (m, 2 H), 2.05 (m, 1 H), 2.44 (m, 1 H),2.55 (s, 3 H), 2.56 (m, 2 H), 2.65 (s, 3 H), 3.05 (m, 2 H), 3.29 (m, 2H), 7.67 (dd, J=8.65, 1.86 Hz, 1 H), 7.75 (d, J=1.86 Hz, 1 H), 7.80 (d,J=8.48 Hz, 1 H), 7.98 (d, J=8.48 Hz, 1 H), 8.29 (d, J=8.81 Hz, 1 H);(DCI/NH₃) m/z 336 (M+H)⁺.

Example 73 ethyl3-methyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-4-isoxazolecarboxylate

The title compound was prepared using the procedure described in Example57 substituting ethyl 5-acetyl-3-methyl-4-isoxazolecarboxylate for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.18 (d, J=6.10Hz, 3 H), 1.19 (t, J=7.12 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m, 2 H), 2.03(m, 1 H), 2.37 (m, 1 H), 2.52 (m, 2 H), 2.53 (s, 3 H), 3.07 (m, 2 H),3.21 (m, 1 H), 3.31 (m, 1 H), 4.29 (q, J=7.12 Hz, 2 H), 7.78 (dd,J=8.82, 2.03 Hz, 1 H), 7.89 (d, J=1.36 Hz, 1 H), 7.98 (d, J=8.48 Hz, 1H), 8.07 (d, J=8.82 Hz, 1 H), 8.45 (d, J=8.82 Hz, 1 H); (DCI/NH₃) m/z394 (M+H)⁺.

Example 744-(7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-3-isoquinolinyl)benzonitrileExample 74A 4-(7-bromo-3-isoquinolinyl)benzonitrile

The product from Example 62D (3.6 mmol), 4-cyanophenylacetylene (4.3mmol), CuI (0.2 mmol), PdCl₂(PPh₃)₂ (0.1 mmol), and diisopropylamine(5.3 mmol) can be combined in toluene (15 mL) and processed as describedin Example 62E to provide the title compound.

Example 74B 4-[7-(2-hydroxyethyl)-3-isoquinolinyl]benzonitrile

The product from Example 74A (4 mmol) is dissolved in 20 mL THF and iscooled to −60° C. under nitrogen. n-BuLi (4.4 mmol) is added dropwise,and the mixture is stirred at −60° C. for additional 30 minutes. Asolution of ethylene oxide (20 mmol) in 10 ml THF is added and themixture is allowed to warm to 10° C. and is stirred to complete thereaction. The mixture is cooled back down to 0° C. and is slowlyquenched with 2N HCl to pH=3. The solvent is removed under vacuum andthe residue is dissolved in 20 mL methylene chloride, is washed withwater, and is concentrated under reduced pressure. The residue ischromatographed on silica gel (5:95 MeOH:CHCl₃) to provide the titlecompound.

Example 74C4-(7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-3-isoquinolinyl)benzonitrile

The product from Example 74B, methanesulfonyl chloride, and(2R)-2-methylpyrrolidine hydrochloride are processed as described inExample 62F to provide the title compound.

Example 756-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxalineand7-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxalineExample 75A N-(4-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}phenyl)acetamide

The product from Example 54B (0.47 g, 2.3 mmol) in acetic acid:water(1:1) at 0° C. was treated with acetic anhydride (0.44 mL, 4.6 mmol) andheated at 100° C. for 45 minutes. The mixture was allowed to cool toroom temperature, concentrated, and the residue was partitioned between1 M NaOH and dichloromethane. The phases were separated and the aqueousphase was extracted with dichloromethane (3 times). The dichloromethanelayers were combined, dried (MgSO₄), filtered, and the filtrate wasconcentrated to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ1.10 (d, J=6 Hz, 3 H), 1.43 (m, 1 H), 1.76 (m, 2 H), 1.92 (m, 1 H), 2.16(s, 3 H), 2.25 (m, 3 H), 2.77 (m, 2 H), 2.99 (m, 1H), 3.23 (td, J=9, 3Hz, 1 H), 7.16 (d, J=8 Hz, 2 H), 7.40 (d, J=8 Hz, 2 H); (DCI/NH₃) m/z247 (M+H)⁺.

Example 75BN-(4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-nitrophenyl)acetamide

The product from Example 75A (0.58 g, 2.4 mmol) in acetic anhydride (2.2mL) and concentrated sulfuric acid (0.16 mL) was cooled to 0° C. andtreated dropwise with 90% nitric acid (0.115 mL, 2.4 mmol). Afterstirring at ambient temperature for 16 hours, the mixture was dilutedwith water, cooled to 0° C., the pH adjusted using 1 M NaOH, andextracted with dichloromethane (3 times). The combined dichloromethanelayers were dried (MgSO₄), filtered, and the filtrate was concentratedto provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 1.08 (d, J=6Hz, 3 H), 1.43 (m, 1 H), 1.74 (m, 2 H), 1.92 (m, 1 H), 2.18 (q, J=9 Hz,1 H), 2.28 (s, 3 H), 2.32 (m, 1 H), 2.84 (m, 2 H), 3.02 (m, 1 H), 3.21(td, J=8, 3 Hz, 1 H), 7.51 (dd, J=9, 2 Hz, 1 H), 8.07 (d, J=2 Hz, 1 H),8.65 (d, J=9 Hz, 1 H), 10.23 (s, 1 H); (DCI/NH₃) m/z 292 (M+H)⁺.

Example 75C 4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-nitroaniline

The product from Example 75B (0.60 g, 2.1 mmol) in 3M HCl (12 mL) washeated at 80° C. for 2 hours, cooled to 0° C., the pH was adjusted bythe slow addition of 1 M NaOH, and extracted with dichloromethane (4times). The combined dichloromethane layers were dried (MgSO₄),filtered, and the filtrate was concentrated to provide the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 1.13 (d, J=6 Hz, 3 H), 1.47 (m, 1H), 1.77 (m, 2 H), 1.95 (m, 1 H), 2.29 (m, 3 H), 2.76 (dd, J=9, 7 Hz, 2H), 3.00 (m, 1 H), 3.25 (td, J=8, 3 Hz, 1 H), 5.97 (s, 2 H), 6.75 (d,J=9 Hz, 1 H), 7.26 (dd, J=9, 2 Hz, 1 H), 7.96 (d, J=2 Hz, 1 H);(DCI/NH₃) m/z 250 (M+H)⁺.

Example 75D 4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1,2-benzenediamine

The title compound was prepared using the procedure described in Example54B substituting the product from Example 75C for the product fromExample 54A to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ1.15 (d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.83 (m, 3 H), 2.30 (m, 3 H), 2.70(m, 2 H), 3.00 (m, 1 H), 3.27 (m, 5 H), 6.59 (m, 3 H); (DCI/NH₃) m/z 220(M+H)⁺.

Example 75E 6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoxaline

The product from Example 75D (14.6 mg, 0.067 mmol) was treated with0.075 mL of a 1 M solution of glyoxal in ethanol (made by diluting 0.4 gof a 40% weight solution of glyoxal in water with ethanol to a totalvolume of 6.9 mL) and heated at 80° C. for 16 hours. The mixture wasallowed to cool to room temperature and concentrated. The residue waschromatographed on silica gel eluting with a gradient of 2% and 3.5%(9:1 MeOH:conc NH₄OH) in dichloromethane to provide the title compound.¹H NMR (300 MHz, CD₃OD) δ 1.15 (d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.80 (m,2 H), 2.03 (m, 1 H), 2.34 (q, J=9 Hz, 1 H), 2.48 (m, 2 H), 3.07 (m, 2H), 3.25 (m, 2 H), 7.80 (dd, J=9, 2 Hz, 1 H), 7.95 (d, J=2 Hz, 1 H),8.04 (d, J=9 Hz, 1 H), 8.84 (d, J=2 Hz, 1 H), 8.86 (d, J=2 Hz, 1 H);(DCI/NH₃) m/z 242 (M+H)⁺.

Example 75F6-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxalineand7-{2-R[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-2-(4-methoxyphenyl)quinoxaline

The product from Example 75D and oxo(4-methoxyphenyl)acetaldehyde(chemical abstracts number 16208-17-6) is processed as described inExample 75E to provide the title compounds.

Example 76 6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-phenylquinoxalineand 7-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-phenylquinoxaline

The product from Example 75D and oxo(phenyl)acetaldehyde is processed asdescribed in Example 75E to provide the title compounds.

Example 776-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinazolineExample 77AN-(2-formyl-4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)nicotinamide

The product from Example 54E (35 mg, 0.15 mmol) and triethylamine (0.051mL, 0.36 mmol) were combined in dichloromethane (0.5 mL) and treatedwith nicotinoyl chloride hydrochloride (30 mg, 0.17 mmol). Afterstirring at ambient temperature for 16 hours, the mixture wasconcentrated and the residue purified by chromatography on silica geleluting with a gradient of 2% and 3.5% (9:1 MeOH:conc NH₄OH) indichloromethane to provide the title compound. ¹H NMR 300 MHz, CDCl₃) δ1.11 (d, J=6 Hz, 3 H), 1.45 (m, 1 H), 1.77 (m, 2 H), 1.94 (m, 1 H), 2.22(q, J=9 Hz, 1 H), 2.35 (m, 2 H), 2.90 (m, 2 H), 3.06 (m, 1 H), 3.25 (m,1 H), 7.48 (dd, J=8, 5 Hz, 1 H), 7.56 (dd, J=8, 2 Hz, 1 H), 7.60 (d, J=2Hz, 1 H), 8.34 (dt, J=8, 2 Hz, 1 H), 8.83 (m, 2 H), 9.32 (d, J=2 Hz, 1H), 9.99 (s, 1 H), 12.09 (s, 1 H); MS (DCI/NH₃) m/z 338 (M+H)⁺.

Example 77B6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinazoline

The product from Example 77A (25 mg, 0.074 mmol) in saturated aqueousammonium chloride (3 mL) was heated at 80° C. for 16 hours. The mixturewas allowed to cool to room temperature, adjusted to pH 14 with 1 MNaOH, and extracted with dichloromethane (3 times). The combineddichloromethane layers were dried (MgSO₄), filtered, and the filtratewas concentrated. The residue was purified by chromatography on silicagel eluting with a gradient of 2% and 3.5% (9:1 MeOH:conc NH₄OH) indichloromethane to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ1.13 (d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.75 (m, 2 H), 1.96 (m, 1 H), 2.25(q, J=9 Hz, 1 H), 2.41 (m, 2 H), 3.10 (m, 3 H), 3.29 (m, 1 H), 7.45 (dd,J=8, 5 Hz, 1 H), 7.78 (d, J=1 Hz, 1 H), 7.83 (dd, J=8, 2 Hz, 1 H), 8.03(d, J=8 Hz, 1 H), 8.73 (d, J=4 Hz, 1 H), 8.85 (dt, J=8, 2 Hz, 1 H), 9.43(d, J=1 Hz, 1 H), 9.80 (s, 1 H); MS (DCI/NH₃) m/z 319 (M+H)⁺.

Example 786-Methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method of Example 31F,substituting1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(2R)-2-methyl-pyrrolidine (Example2B, 60 mg, 0.19 mmol) in place of 2-(6-bromo-naphthalen-2-yl)-ethanol(Example 31E) and substituting 6-methyl-2H-pyridazin-3-one (41.5 mg,0.38 mmol, 2 equiv.) in place of 2H-pyridazin-3-one. Columnchromatography (95:5:trace dichloromethane/methanol/NH₄OH) provided freebase product that was dissolved in Et₂O. HCl gas was bubbled into thissolution to provide the monohydrochloride salt of the title compound (25mg, 34% yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.08 (d, J=2 Hz, 1H), 7.98 (s,1H), 7.95 (s, 1H), 7.88-7.92 (m, 1H), 7.67 (dd, J=2, 8 Hz, 1H), 7.54(dd, J=2, 8 Hz, 1H), 7.48 (d, J=9 Hz, 1H), 7.05 (d, J=9 Hz, 1H),3.85-3.70 (m, 2H), 3.60-3.51 (m, 1H), 3.40-3.15 (m, 4H), 2.42 (s, 3H),2.42-2.26 (m, 1H), 2.25-1.99 (m, 2H), 1.85-1.67 (m, 1H), 1.49 (d, J=6Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 348.

Example 795-{6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine-2-carbonitrileExample 79A 5-Bromo-pyrimidine-2-carbonitrile

A mixture of 5-bromo-2-iodopyrimidine (1.85 g, 6.49 mmol) and CuCN (0.64g, 7.14 mmol, 1.1 equiv.) in pyridine (13 mL) was stirred at 80° C. for3 hours, then an additional 15 hours at room temperature. Volatiles wereremoved under reduced pressure and the residue was partitioned betweendichloromethane and brine. The organic layer was dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (95:5 hexane/ethylacetate) to provide the title intermediate as an off-white solid (0.63g, 53% yield). M.p. 119.6-121.5° C., ¹H NMR (CDCl₃, 300 MHz) δ 8.93 (s,2H). MS (DCI-NH₃) [M+NH₄]⁺ at 201.

Example 79B 5-Trimethylstannanyl-pyrimidine-2-carbonitrile

A mixture of 5-bromo-pyrimidine-2-carbonitrile (Example 79A, 276 mg,1.50 mmol), hexamethylditin (639 mg, 1.95 mmol, 1.3 equiv.) andPd(PPh₃)₄ (55 mg, 0.15 mmol, 0.1 equiv.) in toluene (5 mL) was stirredat reflux for 3 hours, then an additional 15 hours at room temperatureunder a dry nitrogen atmosphere. Volatiles were removed under reducedpressure and the residue was partitioned between dichloromethane andaqueous KF (10 g in 100 mL). The organic layer was dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (100% dichloromethane) toprovide the title intermediate as a white solid (219 mg, 54% yield). ¹HNMR (CDCl₃, 300 MHz) δ 8.81 (s, 2H), 0.45 (s, 9H). MS (DCI-NH₃) [M+H]⁺at 270, [M+NH₄]⁺ at 287.

Example 79C5-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-pyrimidine-2-carbonitrile

A mixture of 5-trimethylstannanyl-pyrimidine-2-carbonitrile (Example79B, 200 mg, 0.75 mmol, 1.1 equiv.), 2-(6-bromo-naphthalen-2-yl)-ethanol(Example 31E, 171 mg, 0.679 mmol), cesium fluoride (227 mg, 1.49 mmol,2.2 equiv.) and Pd[P(t-Bu)₃]₂ (10.4 mg, 0.02 mmol, 0.03 equiv.) inp-dioxane (10 mL) was stirred at 85° C. for 72 hours. Volatiles wereremoved under reduced pressure and the residue was partitioned betweenethyl acetate and aqueous KF (10 g in 100 mL). The organic layer wasdried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography (70:30hexane/ethyl acetate) to provide the title intermediate as a white solid(35.5 mg, 19% yield). ¹H NMR (CD₃OD, 300 MHz) δ 9.33 (s, 2H), 8.31 (d,J=2 Hz, 1H), 7.99 (t, J=9 Hz, 1H), 7.94 (s, 1H), 7.86 (dd, J=2, 9 Hz,1H), 7.79 (br s, 1H), 7.50 (dd, J=2, 9 Hz, 1H), 3.88 (t, J=7 Hz, 2H),3.02 (t, J=7 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 276, [M+NH₄]⁺ at 293.

Example 79D5-{6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine-2-carbonitrile

The title compound was prepared by the methods of Examples 3B and 3Csubstituting5-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-pyrimidine-2-carbonitrile(Example 79C, 35.5 mg, 0.13 mmol) in place of1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone (Example 3A) for themesylate formation and substituting the crude mesylate thus formed (˜45mg, 0.13 mmol) in place of 2-[6-(3-acetylphenyl)-2-naphthyl]ethylmethanesulfonate (Example 3B). Column chromatography (97:3:tracedichloromethane/methanol/NH₄OH) provided free base product that wasdissolved in Et₂O. HCl gas was bubbled into this solution to provide themonohydrochloride salt of the title compound (3.8 mg, 9% yield over twosteps). ¹H NMR (CD₃OD, 300 MHz) δ 9.33 (s, 2H), 8.36 (d, J=2 Hz, 1H),8.06 (dd, J=2, 8 Hz, 2H), 8.07-7.90 (m, 2H), 7.58 (dd, J=2, 8 Hz, 1H),3.85-3.69 (m, 2H), 3.63-3.51 (m, 1H), 3.44-3.18 (m, 4H), 2.43-2.31 (m,1H), 2.25-2.01 (m, 2H), 1.85-1.71 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 343, [M+NH₄]⁺ at 360.

Example 801-{6-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-oneExample 80A 1-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-1H-pyridin-2-one

A mixture of 2-(6-bromo-naphthalen-2-yl)-ethanol (Example 31E, 100 mg,0.40 mmol), 2-hydroxy-pyridine (57 mg, 0.60 mmol, 1.5 equiv.), copperpowder (25 mg, 0.40 mmol), and K₂CO₃ (165 mg, 1.20 mmol, 3 equiv.) inpyridine (2 mL) was stirred at reflux under a dry nitrogen atmospherefor 18 hr. The reaction mixture was cooled to room temperature thenconcentrated under reduced pressure. Residual pyridine was removed byrepeated evaporation with toluene. The residue was partitioned betweenethyl acetate and aqueous NH₄OH (2×50 mL) then washed with brine. Theorganic layer was dried (MgSO₄), filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (100% ethyl acetate) to provide the title intermediate asa white solid (30 mg, 28% yield). ¹H NMR (CDCl₃, 300 MHz) δ 7.80 (d, J=9Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.42 (dd,J=2, 8 Hz, 1H), 7.39-7.30 (m, 3H), 6.62 (dd, J=1, 10 Hz, 1H), 6.20 (dt,J=1, 6 Hz, 1H), 3.84 (t, J=6 Hz, 2H), 2.95 (t, J=6 Hz, 2H). MS (DCI-NH₃)[M+H]⁺ at 266, [M+NH₄]⁺ at 283.

Example 80B1-{6-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-one

Methanesulfonyl chloride (0.01 mL, 0.136 mmol, 1.2 equiv.) was addeddropwise via a syringe to a stirred, −30° C. solution of1-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-1H-pyridin-2-one (Example 80A,30 mg, 0.113 mmol) and Et₃N (0.024 mL, 0.17 mmol, 1.5 equiv.). After twohours stirring at room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and saturated aqueous Na₂CO₃. The organic extract was dried(MgSO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue was crystallized from Et₂O/hexane (20 mg, 52%yield). This mesylate (20 mg, 0.058 mmol), (2R)-2-methylpyrrolidine(14.9 mg, 0.058 mmol, 3.0 equiv.), and cesium carbonate (19 mg, 0.058mmol) in anhydrous acetonitrile (3.5 mL) were stirred in a sealed tubeat 60° C. for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue was partitioned between ethyl acetate andsaturated aqueous Na₂CO₃. The organic layer was dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (97:3:trace,dichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the freebase. This free base was dissolved in Et₂O and HCl gas was bubbled in toprecipitate the hydrochloride salt of the title compound. ¹H NMR (CD₃OD,300 MHz) δ 8.08-7.96 (m, 2H), 7.93 (s, 2H), 7.76-7.66 (m, 2H), 7.60-7.51(m, 2H), 6.70 (d, J=9 Hz, 1H), 6.56 (dt, J=1, 6 Hz, 1H), 3.83-3.68 (m,2H), 3.64-3.49 (m, 1H), 3.43-3.18 (m, 4H), 2.43-2.30 (m, 1H), 2.22-2.02(m, 2H), 1.84-1.69 (m, 1H), 1.49 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at333.

Example 815-{6-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-nicotinonitrileExample 81A 5-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-nicotinonitrile

A mixture of5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (220mg, 0.956 mmol, 1.2 equiv.), 2-(6-bromo-naphthalen-2-yl)-ethanol(Example 31E, 200 mg, 0.8 mmol), Na₂CO₃ (253 mg, 2.39 mmol, 3 equiv.),biphenyl-2-yl-dicyclohexyl-phosphane (7 mg, 0.02 mmol, 0.025 equiv.),and PdCl₂(PPh₃)₂ (27.9 mg, 0.04 mmol, 0.05 equiv.) in isopropanol (20mL) and water (8 mL) was stirred at 80° C. for one hour. The reactionmixture was then concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and saturated aqueous Na₂CO₃. Theorganic layer was dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure to give a crude solid that waspurified by column chromatography (1:1 hexane/ethyl acetate) to providethe title intermediate (166 mg, 76% yield). ¹H NMR (CD₃OD, 300 MHz) δ9.19 (d, J=2 Hz, 1H), 8.88 (d, J=2 Hz, 1H), 8.57 (t, J=2 Hz, 1H), 8.20(d, J=2 Hz, 1H), 7.99-7.90 (m, 2H), 7.79 (dd, J=2, 9 Hz, 1H), 7.76 (brs, 1H), 7.48 (dd, J=2, 9 Hz, 1H), 3.88 (t, J=7 Hz, 2H), 3.02 (t, J=7 Hz,2H). MS (DCI-NH₃) [M+H]⁺ at 275, [M+NH₄]⁺ at 292.

Example 81B Methanesulfonic acid2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester

Methanesulfonyl chloride (0.056 mL, 0.726 mmol, 1.2 equiv.) was added toa stirred, −30° C. solution of5-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-nicotinonitrile (Example 81A,190 mg, 0.539 mmol) under a dry nitrogen atmosphere. Triethylamine (0.13mL, 0.908 mmol, 1.5 equiv.) was added dropwise to the chilled solution,then the reaction mixture was stirred at room temperature for 18 hours.The reaction mixture was partitioned between ethyl acetate and saturatedaqueous Na₂CO₃. The organic layer was dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure to give the titleintermediate (192 mg, 90% yield). ¹H NMR (CDCl₃, 300 MHz) δ 9.22 (d, J=2Hz, 1H), 8.90 (d, J=2 Hz, 1H), 8.60 (t, J=2 Hz, 1H), 8.25 (br s, 1H),8.00 (t, J=8 Hz, 2H), 7.87-7.81 (m, 2H), 7.52 (dd, J=2, 8 Hz, 1H),7.31-7.25 (m, 1H), 4.55 (t, J=6 Hz, 2H), 3.25 (t, J=6 Hz, 2H), 2.95 (s,3H). MS (DCI-NH₃) [M+H]⁺ at 353, [M+NH₄]⁺ at 370.

Example 81C5-{6-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-nicotinonitrile

Methanesulfonic acid 2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethylester (Example 81B, 190 mg, 0.54 mmol), (2R)-2-methylpyrrolidine (138mg, 1.62 mmol, 3.0 equiv.), and cesium carbonate (176 mg, 0.54 mmol) inanhydrous acetonitrile (6 mL) were stirred in a sealed tube at 50° C.for 18 hours. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between ethyl acetate andsaturated aqueous Na₂CO₃. The organic layer was washed with brine, thendried (MgSO₄), and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography(98:2:trace dichloromethane/methanol/NH₄OH). Fractions containingproduct were combined and concentrated under reduced pressure to providethe free base of the title compound as a white solid (105.9 mg, 57%yield). This free base was dissolved in methanol and treated with excessdioxane-HCl. Ether was added to induce crystallization of thedihydrochloride salt of the title compound. ¹H NMR (CD₃OD, 300 MHz) δ9.26 (br s, 1H), 8.97 (br s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.05 (s,1H), 8.02 (s, 1H), 7.90 (br s, 1H), 7.88 (dd, J=2, 9 Hz, 1H), 7.56 (d,J=8 Hz, 1H), 3.84-3.49 (m, 7H), 2.45-2.30 (m, 1H), 2.27-1.99 (m, 2H),1.84-1.69 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 342.

Example 824-Methyl-1-{6-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-oneExample 82A1-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-4-methyl-1H-pyridin-2-one

A mixture of 2-(6-bromo-naphthalen-2-yl)-ethanol (Example 31E, 200 mg,0.796 mmol), 2-hydroxy-4-methyl-pyridine (130 mg, 1.195 mmol, 1.5equiv.), copper powder (50.6 mg, 0.796 mmol), and K₂CO₃ (330.2 mg, 2.389mmol, 3 equiv.) in pyridine (5 mL) was stirred at reflux under a drynitrogen atmosphere for 62 hr. The reaction mixture was cooled to roomtemperature then concentrated under reduced pressure. Residual pyridinewas removed by repeated evaporation with toluene. The residue waspartitioned between ethyl acetate and aqueous NH₄OH then washed withbrine (3×50 mL). The organic layer was dried (MgSO₄), filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (100% ethyl acetate) to provide thetitle intermediate as a white solid (70 mg, 31% yield). ¹H NMR (CD₃OD,300 MHz) δ 7.94 (d, J=9 Hz, 1H), 7.88 (d, J=9 Hz, 1H), 7.84 (d, J=2 Hz,1H), 7.80 (br s, 1H), 7.59 (d, J=7 Hz, 1H), 7.49 (dd, J=2, 9 Hz, 1H),7.44 (dd, J=2, 9 Hz, 1H), 6.49 (br s, 1H), 6.40 (dd, J=2, 7 Hz, 1H),3.87 (t, J=7 Hz, 2H), 3.04 (t, J=7 Hz, 2H), 2.32 (s, 3H). MS (DCI-NH₃)[M+H]⁺ at 280.

Example 82B4-Methyl-1-{6-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-1H-pyridin-2-one

Methanesulfonyl chloride (0.03 mL, 0.301 mmol, 1.2 equiv.) was addeddropwise via a syringe to a stirred, 0° C. solution of1-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-4-methyl-1H-pyridin-2-one(Example 82A, 70 mg, 0.251 mmol) in anhydrous THF (10 mL) under a drynitrogen atmosphere. Triethylamine (1.0 mL, 7.175 mmol, 28.6 equiv.) wasthen added. After two hours of stirring at 0° C., the reaction mixturewas concentrated under reduced pressure. The residue was partitionedbetween EtOAc and saturated aqueous Na₂CO₃. The organic extract wasdried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure. This crude mesylate (˜89 mg, 0.249 mmol),(2R)-2-methylpyrrolidine (64 mg, 0.747 mmol, 3.0 equiv.), and cesiumcarbonate (81 mg, 0.249 mmol) in anhydrous acetonitrile (5 mL) werestirred in a sealed tube at 50° C. for 18 hours. The reaction mixturewas concentrated under reduced pressure. The residue was partitionedbetween ethyl acetate and saturated aqueous Na₂CO₃. The organic layerwas dried (MgSO₄) and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(97:3:trace dichloromethane/methanol/NH₄OH). Fractions containingproduct were combined and concentrated under reduced pressure to providethe free base.

This free base was dissolved in Et₂O and the solution was treated withHCl-dioxane to precipitate the hydrochloride salt of the title compound(15 mg, 16% yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.00 (d, J=9 Hz, 1H), 7.98(d, J=9 Hz, 1H), 7.93-7.89 (m, 2H), 7.62 (d, J=7 Hz, 1H), 7.56 (dd, J=2,9 Hz, 1H), 7.51 (dd, J=2, 9 Hz, 1H), 6.52 (br s, 1H), 6.45 (dd, J=2, 7Hz, 1H), 3.83-3.68 (m, 2H), 3.61-3.49 (m, 1H), 3.43-3.17 (m, 4H),2.43-2.30 (m, 1H), 2.33 (s, 3H), 2.24-1.99 (m, 2H), 1.83-1.69 (m, 1H),1.49 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 347.

Example 832-{6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrazineExample 83A 2-(6-Pyrazin-2-yl-naphthalen-2-yl)-ethanol

A mixture of 2-tributylstannanyl-pyrazine (323 mg, 0.876 mmol, 1.1equiv.), 2-(6-bromo-naphthalen-2-yl)-ethanol (Example 31E, 200 mg, 0.796mmol), cesium fluoride (266 mg, 1.75 mmol, 2.2 equiv.) and Pd[P(t-Bu)₃]₂(12.2 mg, 0.024 mmol, 0.03 equiv.) in p-dioxane (10 mL) was stirred at85° C. for 2.5 hours. Volatiles were removed under reduced pressure andthe residue was partitioned between ethyl acetate and aqueous KF (10 gin 100 mL). The organic layer was washed consecutively with saturatedaqueous Na₂CO₃ and brine, then dried (MgSO₄) and filtered. The filtratewas concentrated under reduced pressure and the residue was purified bycolumn chromatography (1:1 hexane/ethyl acetate) to provide the titleintermediate as a beige solid (42.5 mg, 21% yield). ¹H NMR (CD₃OD, 300MHz) δ 9.25 (d, J=1 Hz, 1H), 8.72-8.70 (m, 1H), 8.58 (d, J=2 Hz, 1H),8.54 (d, J=3 Hz, 1H), 8.17 (dd, J=2, 9 Hz, 1H), 7.97 (d, J=2 Hz, 1H),7.94 (d, J=2 Hz, 1H), 7.77 (br s, 1H), 7.48 (dd, J=2, 8 Hz, 1H), 3.88(t, J=7 Hz, 2H), 3.02 (t, J=7 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 251,[M+NH₄]⁺ at 268.

Example 83B2-{6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrazine

Methanesulfonyl chloride (0.005 mL, 0.067 mmol, 1.2 equiv.) was addeddropwise via a syringe to a stirred, 0° C. solution of2-(6-pyrazin-2-yl-naphthalen-2-yl)-ethanol (Example 83A, 14 mg, 0.056mmol) in anhydrous THF (10 mL) under a dry nitrogen atmosphere.Triethylamine (0.023 mL, 0.167 mmol, 3 equiv.) was then added. After 18hours at −20° C., the reaction mixture was dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure. This crudemesylate (˜18 mg, 0.056 mmol), (2R)-2-methylpyrrolidine (190 mg, 2.237mmol, 40 equiv.), and cesium carbonate (182 mg, 0.559 mmol, 10 equiv.)in anhydrous acetonitrile (5 mL) were stirred in a sealed tube at 40° C.for 62 hours. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between ethyl acetate andsaturated aqueous Na₂CO₃. The organic layer was dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH). Fractions containing product werecombined and concentrated under reduced pressure to provide the freebase. This free base was dissolved in methanol and the solution wastreated with HCl gas. The hydrochloride salt of the title compound wasobtained on evaporation of solvent (4.5 mg, 23% yield). ¹H NMR (CD₃OD,300 MHz) δ 9.29 (br s, 1H), 8.79-8.74 (m, 1H), 8.64 (br s, 1H), 8.58 (d,J=2 Hz, 1H), 8.24 (dd, J=2, 9 Hz, 1H), 8.03 (t, J=9 Hz, 2H), 7.90 (br s,1H), 7.55 (dd, J=2, 9 Hz, 1H), 3.84-3.68 (m, 2H), 3.64-3.49 (m, 1H),3.44-3.17 (m, 4H), 2.43-2.30 (m, 1H), 2.27-2.00 (m, 2H), 1.84-1.68 (m,1H), 1.50 (d, J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 318.

Example 842-{6-[2-((2R)-2-Methyl-2,5-dihydro-pyrrol-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-oneExample 84A (2S)-2-Hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester

The title intermediate can be prepared reductively from thecorresponding carboxylic acid or its methyl ester.

From the carboxylic acid: Employing the literature (Rodriguez, M., et.al., Tetrahedron Letters, 1991, 32 (7), 923-926) procedure;2,5-Dihydro-pyrrole-1, (2R)-2-dicarboxylic acid 1-tert-butyl ester (970mg, 4.549 mmol) was dissolved in anhydrous DME (5 mL). This solution waschilled to −20° C. under a dry nitrogen atmosphere. To this stirredsolution was slowly added first 4-methyl-morpholine (0.5 mL, 4.549 mmol)then isobutyl chloroformate (0.6 mL, 4.549 mmol). After stirring at −20°C. for one minute, a solution of sodium borohydride (516 mg, 13.647mmol, 3 equiv.) in water (5 mL) was rapidly added and stirring wascontinued while the reaction mixture warmed to −5° C. where it wasmaintained for 25 minutes. The reaction mixture was then diluted withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried (MgSO₄), and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by columnchromatography (4:1 hexane/ethyl acetate) to give the title intermediate(386 mg, 42% yield). ¹H NMR (CDCl₃, 300 MHz) δ 5.90-5.72 (m, 1H),5.69-5.56 (m, 1H), 4.80-4.60 (m, 1H), 4.28-3.99 (m, 2H), 3.78 (dd, J=2,9 Hz, 1H), 3.65-3.51 (m, 1H), 1.49 (s, 9H). MS (DCI-NH₃) [M+H]⁺ at 200,[M+NH₄]⁺ at 217.

From the methyl carboxylate: Sodium borohydride (333 mg, 8.80 mmol, 2equiv.) was added in one lot to a stirred, 0° C. solution of2,5-dihydro-pyrrole-1, (2R)-2-dicarboxylic acid 1-tert-butyl ester2-methyl ester (1.0 g, 4.40 mmol) in THF (3 mL) and methanol (2 mL). Thereaction mixture was stirred at 0° C. for 15 min then at roomtemperature for 18 hr. After an aqueous work-up as above and columnchromatography as above the title intermediate was obtained (524 mg, 60%yield).

Example 84B (2R)-2-Methyl-2,5-dihydro-pyrrole-1-carboxylic acidtert-butyl ester

Methanesulfonyl chloride (0.24 mL, 3.13 mmol, 1.2 equiv.) was addeddropwise to a stirred, 0° C. solution of(2S)-2-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butylester (Example 84A, 520 mg, 2.61 mmol) and triethylamine (1.1 mL, 7.83mmol, 3 equiv.) in anhydrous THF (50 mL) under a dry nitrogenatmosphere. The reaction mixture was stirred at 0° C. for 15 min then atroom temperature for 18 hours. The reaction mixture was concentratedunder reduced pressure and the residue was partitioned between ethylacetate and water. The organic layer was washed with saturated aqueousNa₂CO₃, then dried (MgSO₄), and filtered. The filtrate was concentratedunder reduced pressure and the crude mesylate (˜660 mg, 91% yield) wasimmediately reduced:

A solution of the crude mesylate (˜660 mg, 2.38 mmol) in THF (10 mL) wasstirred at 0° C. under a dry nitrogen atmosphere. Lithiumtriethylborohydride (1.0 M in THF, 7.14 mL, 7.14 mmol, 3 equiv.) wasadded dropwise. Stirring at 0° C. was continued for 20 min after theaddition, then the reaction mixture was stirred at room temperature for18 hours. The reaction was quenched by the careful, sequential additionof water (1.38 mL), 3 N NaOH (2.75 mL), and 30% aqueous hydrogenperoxide (2.75 mL). After stirring for 30 min, the reaction was treatedwith saturated aqueous Na₂SO₃ and stirred vigorously overnight. Theorganic layer was dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (gradient:100% hexane to 95:5 hexane/ethylacetate) to provide the title intermediate (282 mg, 65% yield). ¹H NMR(CDCl₃, 300 MHz) δ 5.77-5.62 (m, 2H), 4.63-4.42 (m, 1H), 4.27-3.98 (m,2H), 1.48 (s, 9H), 1.34-1.19 (m, 3H). MS (DCI-NH₃) [M+H]⁺ at 184,[M+NH₄]⁺ at 201.

Example 84C (2R)-2-Methyl-2,5-dihydro-1H-pyrrole

Trifluoroacetic acid (1.8 mL, 22.92 mmol, 15 equiv.) was added dropwiseto a stirred, room temperature solution of(2R)-2-methyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester(Example 84B, 280 mg, 1.528 mmol) in dichloromethane (5 mL). Thereaction mixture was stirred at room temperature under a dry nitrogenatmosphere for 18 hours. The reaction mixture was concentrated underreduced pressure to give the crude title intermediate as itstrifluoroacetic acid salt (˜300 mg, 100% yield). ¹H NMR (CD₃OD, 300 MHz)δ 5.92 (s, 2H), 4.9-4.49 (m, 1H), 4.12-3.97 (m, 2H), 1.44 (d, J=7 Hz,3H). MS (DCI-NH₃) [M+H]⁺ at 84.

Example 84D2-{6-[2-((2R)-2-Methyl-2,5-dihydro-pyrrol-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

A mixture of methanesulfonic acid2-[6-(6-oxo-6H-pyridazin-1-yl)-naphthalen-2-yl]-ethyl ester (Example31G, 205 mg, 0.595 mmol), (2R)-2-methyl-2,5-dihydro-1H-pyrrole,trifluoroacetic acid salt (Example 84C, ˜300 mg, 1.52 mmol, 2.55equiv.), and cesium carbonate (1.49 g, 4.56 mmol, 3 equiv.) in anhydrousacetonitrile (10 mL) was stirred in a sealed tube at room temperaturefor 90 hours then at 45° C. for another 18 hours. The reaction mixturewas concentrated under reduced pressure. The residue was partitionedbetween ethyl acetate and saturated aqueous Na₂CO₃. The aqueous layerwas washed with ethyl acetate, and the combined organic extracts weredried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography(98:2:trace dichloromethane/methanol/NH₄OH). Fractions containingproduct were combined and concentrated under reduced pressure to providethe free base product (69 mg, 35% yield). ¹H NMR (CD₃OD, 300 MHz) δ 8.04(dd, J=2, 4 Hz, 1H), 8.04 (d, J=2 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 7.88(d, J=9 Hz, 1H), 7.79 (br s, 1H), 7.62 (dd, J=2, 9 Hz, 1H), 7.51 (dd,J=3, 9 Hz, 1H), 7.48 (dd, J=2, 9 Hz, 1H), 7.12 (dd, J=2, 9 Hz, 1H),5.83-5.68 (m, 2H), 3.91-3.81 (m, 1H), 3.66-3.54 (m, 1H), 3.40-3.30 (m,1H), 3.21-3.08 (m, 1H), 3.08-2.91 (m, 2H), 2.86-2.73 (m, 1H), 1.22 (d,J=7 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 332.

Example 854-(6-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-ethyl}-naphthalen-2-yl)-benzonitrileExample 85A Methanesulfonic acid2-[6-(4-cyano-phenyl)-naphthalen-2-yl]-ethyl ester

A stirred, 0° C. solution of4-[6-(2-hydroxyethyl)-2-naphthyl]benzonitrile (Example 1F, 460 mg, 1.683mmol) and triethylamine (0.94 mL, 6.732 mmol, 4 equiv.) in anhydrous THF(10 mL) was treated with methanesulfonyl chloride (0.17 mL, 2.188 mmol,1.3 equiv.) under a dry nitrogen atmosphere. The reaction mixture wasstirred at room temperature for one hour, then the reaction mixture wasdiluted with water and extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were washed with saturated aqueous Na₂CO₃ andthen with brine. The organic layer was dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure to give the titleintermediate (305 mg, 52% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.04 (d, J=2Hz, 1H), 7.94-7.87 (m, 2H), 7.84-7.69 (m, 6H), 7.43 (dd, J=2, 8 Hz, 1H),4.54 (t, J=7 Hz, 2H), 3.26 (t, J=7 Hz, 2H), 2.88 (s, 3H). MS (DCI-NH₃)[M+NH₄]⁺ at 369.

Example 85B4-(6-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-ethyl}-naphthalen-2-yl)-benzonitrile

A mixture of methanesulfonic acid2-[6-(4-cyano-phenyl)-naphthalen-2-yl]-ethyl ester (Example 85A, 150 mg,0.427 mmol) and N,N,N′-trimethylethylenediamine (0.17 mL, 1.280 mmol, 3equiv.) in anhydrous acetonitrile (1 mL) was stirred at room temperaturein a sealed tube for 66 hours. The reaction mixture was partitionedbetween ethyl acetate and saturated aqueous Na₂CO₃. The organic layerwas dried (MgSO₄) and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(gradient: 98:2 to 97:3:trace dichloromethane/methanol/NH₄OH) to givethe free base product (28.7 mg, 19% yield). The free base was dissolvedin methanol and treated with a methanol solution containing oneequivalent of L-tartaric acid. The tartrate salt of the title compoundcrystallized from the methanol solution. ¹H NMR (CD₃OD, 300 MHz) δ 8.17(d, J=2 Hz, 1H), 7.97-7.82 (m, 4H), 7.86-7.77 (m, 4H), 7.48 (dd, J=2, 8Hz, 1H), 4.39 (s, tartrate, 2H), 3.17-2.90 (m, 8H), 2.69 (s, 6H), 2.54(s, 3H). MS (DCI-NH₃) [M+H]⁺ at 358.

Example 864-{6-[2-(4-Methyl-piperazin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile

A mixture of methanesulfonic acid2-[6-(4-cyano-phenyl)-naphthalen-2-yl]-ethyl ester (150 mg, 0.427 mmol)and 1-methylpiperazine (0.14 mL, 1.280 mmol, 3 equiv.) in anhydrousacetonitrile (1 mL) was stirred at room temperature in a sealed tube for66 hours. The reaction mixture was partitioned between ethyl acetate andsaturated aqueous Na₂CO₃. The organic layer was dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (97:3:tracedichloromethane/methanol/NH₄OH) to give the free base product. ¹H NMR(CD₃OD, 300 MHz) δ 8.16 (br s, 1H), 7.97-7.89 (m, 4H), 7.86-7.81 (m,2H), 7.79 (dd, J=2, 8 Hz, 2H), 7.74 (br s, 1H), 7.44 (dd, J=2, 8 Hz,1H), 3.05-2.97 (m, 2H), 2.77-2.43 (m, 10H), 2.31 (s, 3H). MS (DCI-NH₃)[M+H]⁺ at 356. The free base was dissolved in methanol and treated witha methanol solution containing one equivalent of L-tartaric acid. Thetartrate salt of the title compound crystallized from the methanolsolution (101 mg, 66% yield).

Example 872-(2,5-Dimethyl-furan-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(2,5-dimethyl-furan-3-yl)-ethanone for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.19 (d, J=6Hz, 3 H), 1.51 (m, 1 H), 1.84 (m, 2 H), 2.06 (m, 1 H), 2.31 (s, 3 H),2.48 (m, 3 H), 2.63 (s, 3 H), 3.06 (m, 3 H), 3.21 (m, 1 H), 7.33 (d, J=9Hz, 1 H), 7.34 (d, J=3 Hz, 1 H), 7.72 (dd, J=9 Hz, J=3 Hz, 1 H), 7.82(s, 1 H), 8.16 (d, J=9 Hz, 1 H), 8.39 (d, J=3 Hz, 1 H); (DCI/NH₃) m/z335 (M+H)⁺.

Example 886-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-methylsulfanyl-phenyl)-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(4-methylsulfanyl-phenyl)ethanone for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.17 (d, J=6Hz, 3 H), 1.48 (m, 1 H), 1.84 (m, 2 H), 2.05 (m, 1 H), 2.49 (m, 3 H),2.55 (s, 3 H), 2.63 (s, 3 H), 3.06 (m, 2 H), 3.17 (m, 1 H), 3.21 (m, 1H), 7.41 (d, J=9 Hz, 2 H), 7.68 (dd, J=9 Hz, J=3 Hz, 1 H), 7.77 (d, J=3Hz, 1 H), 7.94 (d, J=9 Hz, 1 H), 8.03 (d, J=9 Hz, 1 H), 8.05 (d, J=9 Hz,1 H), 8.33 (d, J=9 Hz, 1 H); (DCI/NH₃) m/z 363 (M+H)⁺.

Example 892-(6-Methyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(6-methyl-pyridin-3-yl)-ethanone (reference: S. P. Tanis etal., J. Med. Chem. 39, 1996, 5053-5063) for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.17 (d, J=6Hz, 3 H), 1.48 (m, 1 H), 1.84 (m, 2 H), 2.04 (m, 1 H), 2.38 (m, 1 H),2.49 (m, 3 H), 2.63 (s, 3 H), 3.06 (m, 2 H), 3.19 (m, 1 H), 7.47 (d, J=9Hz, 1 H), 7.70 (dd, J=9 Hz, J=3 Hz, 1 H), 7.80 (d, J=3 Hz, 1 H), 8.00(d, J=9 Hz, 1 H), 8.07 (d, J=9 Hz, 1 H), 8.37 (d, J=9 Hz, 1 H), 8.47(dd, J=9 Hz, J=3 Hz, 1 H), 9.17 (d, J=3 Hz, 1 H); (DCI/NH₃) m/z 332(M+H)⁺.

Example 902-(1,3-Dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)ethanone (reference: P.Schenone et al., J. Heterocycl. Chem. 19, 1982, 1355-1361) for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.32 (d, J=6Hz, 3 H), 1.63 (m, 1 H), 1.97 (m, 2 H), 2.17 (m, 1 H), 2.60 (s, 3 H),2.85 (m, 2 H), 3.12 (m, 3 H), 3.47 (m, 2 H), 3.90 (s, 3 H), 7.66 (dd,J=9 Hz, J=3 Hz, 1 H), 7.69 (d, J=9 Hz, 1 H), 7.76 (d, J=2 Hz, 1 H), 7.96(d, J=9 Hz, 1 H), 8.12 (s, 1 H), 8.22 (d, J=9 Hz, 1 H); (DCI/NH₃) m/z335 (M+H)⁺.

Example 916-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-3-yl-quinoline

The title compound was prepared using the procedure described in Example57 using 1-thiophen-3-yl-ethanone (reference: E. Campaigne et al., J.Amer. Chem. Soc. 70, 1948, 1555) for 1-(1,3-thiazol-2-yl)-ethanone. ¹HNMR (300 MHz, CD₃OD) δ 1.27 (d, J=6 Hz, 3 H), 1.61 (m, 1 H), 1.92 (m, 2H), 2.12 (m, 1 H), 2.70 (m, 2 H), 3.06 (m, 3 H), 3.24 (m, 1 H), 3.45 (m,1 H), 7.56 (dd, J=9 Hz, J=9 Hz, 1 H), 7.68 (dd, J=9 Hz, J=3 Hz, 1 H),7.78 (s, 1 H), 7.88 (d, J=6 Hz, 1 H), 7.94 (d, J=9 Hz, 1 H), 8.03 (d,J=9 Hz, 1 H), 8.18 (m, 1 H), 8.28 (d, J=9 Hz, 1 H); (DCI/NH₃) m/z 323(M+H)⁺.

Example 926-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-pyrimidin-5-yl-quinoline

The title compound was prepared using the procedure described in Example57 using 1-pyrimidin-5-yl-ethanone (reference: I. I. Naumenko et al.,Chem. Heterocycl. Compd. (Engl. Transl.) 17, 1981, 710-714) for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.16 (d, J=6Hz, 3 H), 1.50 (m, 1 H), 1.84 (m, 2 H), 2.04 (m, 1 H), 2.35 (m, 1 H),2.46 (m, 2 H), 3.12 (m, 3 H), 3.21 (m, 1 H), 7.74 (dd, J=9 Hz, J=3 Hz, 1H), 7.82 (d, J=3 Hz, 1 H), 8.10 (d, J=6 Hz, 2 H), 8.43 (d, J=9 Hz, 1 H),9.25 (s, 1 H), 9.56 (s, 2 H); (DCI/NH₃) m/z 319 (M+H)⁺.

Example 932-(2,6-Dimethyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(2,6-dimethyl-pyridin-3-yl)ethanone (reference K. FrankeAngew. Chem. 67, 1955, 395) for 1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR(300 MHz, CD₃OD) δ 1.17 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m, 2 H),2.01 (m, 1 H), 2.35 (m, 1 H), 2.47 (m, 2 H), 2.54 (s, 3 H), 2.59 (s, 3H), 3.07 (m, 3 H), 3.19 (m, 1 H), 7.29 (d, J=9 Hz, 1 H), 7.63 (d, J=9Hz, 1 H), 7.73 (dd, J=9 Hz, J=3 Hz, 1 H), 7.81 (d, J=6 Hz, 1 H), 7.84(d, J=3 Hz, 1 H), 8.00 (d, J=9 Hz, 1 H), 8.40 (d, J=9 Hz, 1 H);(DCI/NH₃) m/z 346 (M+H)⁺.

Example 941-[2,6-Dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-pyridin-3-yl]-ethanone

The title compound was prepared using the procedure described in Example57 using 3,5-diacetyl-2,6-dimethylpyridine for1-(1,3-thiazol-2-yl)ethanone. The product was dissolved in water andtreated with two equivalents of L-tartaric acid. The solvent was removedvia lypholization to give the ditartrate salt of the product as a whitefoam. ¹H NMR (CD₃OD) δ ppm 1.49 (d, J=6.78 Hz, 3 H), 1.81 (m, 1 H), 2.13(m, 2 H), 2.35 (m, 1 H), 2.60 (s, 3 H), 2.64 (s, 3 H), 2.76 (s, 3 H),3.36 (m, 4 H), 3.59 (m, 1 H), 3.74 (m, 2 H), 4.47 (s, 4 H), 7.77 (d,J=8.48 Hz, 1 H), 7.82 (dd, J=8.65, 1.87 Hz, 1 H), 7.99 (d, J=1.70 Hz, 1H), 8.10 (d, J=8.82 Hz, 1 H), 8.32 (s, 1 H), 8.47 (d, J=8.48 Hz, 1 H).MS (DCI-NH₃) [M+H]⁺ at 388.

Example 956-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2H-pyrazol-3-yl)-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(1H-pyrazol-5-yl)ethan-1-one hydrochloride for1-(1,3-thiazol-2-yl)ethanone and using 5 drops of the saturated solutionof potassium hydroxide in ethanol. ¹H NMR (CDCl₃) δ ppm 1.14 (d, J=6.10Hz, 3 H), 1.48 (m, 1 H), 1.77 (m, 2 H), 1.93 (m, 1 H), 2.25 (q, J=8.82Hz, 1 H), 2.40 (m, 2 H), 3.01 (m, 2 H), 3.14 (m, 1 H), 3.30 (m, 1 H),6.92 (s, 1 H), 7.61 (m, 1 H), 7.63 (s, 1 H), 7.70 (d, J=2.03 Hz, 1 H),7.81 (d, J=8.82 Hz, 1 H), 8.02 (d, J=8.48 Hz, 1 H), 8.14 (d, J=8.48 Hz,1 H). MS (DCI-NH₃) [M+H]⁺ at 307.

Example 962-(3-Bromo-isoxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(3-bromo-isoxazol-5-yl)-ethanone (reference: M. D. Amici etal., J. Org. Chem. 1989, 54 (11), 2646-2650) for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (CDCl₃) δ ppm 1.13 (d, J=6.10 Hz, 3H), 1.47 (m, 1 H), 1.78 (m, 2 H), 1.95 (m, 1 H), 2.24 (q, J=8.59 Hz, 1H), 2.40 (m, 2 H), 3.08 (m, 3 H), 3.29 (m, 1 H), 7.14 (s, 1 H), 7.67(dd, 1 H), 7.69 (s, 1 H), 7.96 (d, J=8.48 Hz, 1 H), 8.06 (d, J=9.16 Hz,1 H), 8.24 (d, J=8.48 Hz, 1 H). MS (DCI-NH₃) [M+H]⁺ at 386.

Example 972-(6-Chloro-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(6-chloro-3-pyridinyl)-1-ethanone for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (CDCl₃) δ ppm 1.14 (d, J=5.76 Hz, 3H), 1.47 (m, 1 H), 1.78 (m, 2 H), 1.94 (m, 1 H), 2.25 (q, J=8.70 Hz, 1H), 2.40 (m, 2 H), 3.03 (m, 2 H), 3.15 (m, 1 H), 3.30 (m, 1 H), 7.48 (d,J=8.48 Hz, 1 H), 7.65 (dd, 1 H), 7.67 (s, 1 H), 7.83 (d, J=8.48 Hz, 1H), 8.08 (d, J=8.48 Hz, 1 H), 8.21 (d, J=8.48 Hz, 1 H), 8.51 (dd,J=8.31, 2.54 Hz, 1 H), 9.11 (dd, J=2.71, 0.68 Hz, 1 H). MS (DCI-NH₃)[M+H]⁺ at 352.

Example 982-(3,5-Dimethyl-thiophen-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(3,5-dimethyl-2-thienyl)ethan-1-one for1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (CDCl₃) δ ppm 1.14 (d, J=6.10 Hz, 3H), 1.47 (m, 1 H), 1.77 (m, 2 H), 1.95 (m, 1 H), 2.25 (m, 1 H), 2.39 (m,2 H), 2.49 (s, 3 H), 2.54 (s, 3 H), 3.00 (m, 2 H), 3.11 (m, 1 H), 3.29(m, 1 H), 6.64 (s, 1 H), 7.56 (dd, 1 H), 7.58 (s, 1H), 7.63 (d, J=8.82Hz, 1 H), 7.99 (d, J=8.14 Hz, 1 H), 8.05 (d, J=8.82 Hz, 1 H). MS(DCI-NH₃) [M+H]⁺ at 351.

Example 996-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-2-yl-quinoline

The title compound was prepared using the procedure described in Example57 using 2-acetylthiophene for 1-(1,3-thiazol-2-yl) ethanone. ¹H NMR(CDCl₃) δ ppm 1.15 (d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.77 (m, 2 H),1.96 (m, 1 H), 2.26 (q, J=8.70 Hz, 1 H), 2.41 (m, 2 H), 3.02 (m, 2 H),3.14 (m, 1 H), 3.30 (m, 1 H), 7.15 (dd, J=5.09, 3.73 Hz, 1 H), 7.45 (dd,J=5.09, 1.02 Hz, 1 H), 7.58 (dd, 1H), 7.59 (s, 1 H), 7.71 (dd, J=3.73,1.02 Hz, 1 H), 7.77 (d, J=8.82 Hz, 1 H), 8.01 (d, J=8.48 Hz, 1 H), 8.08(d, J=8.82 Hz, 1 H). MS (DCI-NH₃) [M+H]⁺ at 323.

Example 1002-Furan-3-yl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-furan-3-yl-ethanone (reference: J. M. McNamara et al.,Tetrahedron 1984, 40 (22), 4685-4692) for 1-(1,3-thiazol-2-yl)ethanone.¹H NMR (CDCl₃) δ ppm 1.14 (d, J=6.10 Hz, 3 H), 1.47 (m, 1 H), 1.77 (m, 2H), 1.95 (m, 1 H), 2.25 (q, J=8.82 Hz, 1 H), 2.40 (m, 2 H), 3.01 (m, 2H), 3.14 (m, 1 H), 3.35 (m, 1 H), 7.10 (dd, J=1.87, 0.85 Hz, 1 H), 7.54(t, J=1.70 Hz, 1 H), 7.57 (d, J=8.48 Hz, 1 H), 7.58 (dd, 1 H), 7.60 (s,1 H), 8.00 (d, J=8.14 Hz, 1 H), 8.07 (d, J=7.80 Hz, 1 H), 8.13 (m, 1 H).MS (DCI-NH₃) [M+H]⁺ at 307.

Example 1012-(4,5-Dihydro-thiazol-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 2-acetyl-2-thiazoline for 1-(1,3-thiazol-2-yl)ethanone. ¹H NMR(CDCl₃) δ ppm 1.13 (d, J=6.10 Hz, 3 H), 1.46 (m, 1 H), 1.76 (m, 2 H),1.94 (m, 1 H), 2.24 (q, J=8.59 Hz, 1 H), 2.40 (m, 2 H), 3.02 (m, 2 H),3.13 (m, 1 H), 3.29 (m, 1 H), 3.41 (t, J=8.48 Hz, 2 H), 4.60 (t, J=8.48Hz, 2 H), 7.63 (dd, J=8.48, 2.03 Hz, 1 H), 7.65 (s, 1 H), 8.11 (d,J=8.82 Hz, 1 H), 8.13 (s, 2 H). MS (DCI-NH₃) [M+H]⁺ at 326.

Example 1021-[4-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-phenyl]-ethanone

The title compound was prepared using the procedure described in Example57 using 1,4-diacetylbenzene for 1-(1,3-thiazol-2-yl)ethanone. ¹H NMR(CDCl₃) δ ppm 1.15 (d, J=5.76 Hz, 3 H), 1.48 (m, 1 H), 1.79 (m, 2 H),1.95 (m, 1 H), 2.26 (q, 1 H), 2.42 (m, 2 H), 2.67 (s, 3 H), 3.04 (m, 2H), 3.15 (m, 1 H), 3.31 (m, 1 H), 7.64 (dd, J=8.48, 2.03 Hz, 1 H), 7.67(s, 1 H), 7.90 (d, J=8.48 Hz, 1 H), 8.11 (m, 3 H), 8.20 (d, J=8.48 Hz, 1H), 8.27 (m, 2 H). MS (DCI-NH₃) [M+H]⁺ at 359.

Example 1033-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-2-trifluoromethyl-pyridin-4-ol

The title compound was prepared using the procedure described in Example57 using 1-(4-hydroxy-2-trifluoromethyl-pyridin-3-yl)ethanone(reference: L. S. Vasil'ev et al., Russ. Chem. Bl. 1996, 45 (11),2574-2577) for 1-(1,3-thiazol-2-yl)ethanone. ¹H NMR (CD₃OD) δ ppm 1.43(d, J=6.44 Hz, 3 H), 1.73 (m, 1 H), 2.06 (m, 2 H), 2.29 (m, 1 H),3.10-3.75 (m, 7 H), 6.93 (d, J=5.76 Hz, 1 H), 7.52 (d, J=8.48 Hz, 1 H),7.70 (dd, J=8.65, 1.87 Hz, 1 H), 7.88 (d, J=1.70 Hz, 1 H), 8.01 (d,J=8.82 Hz, 1 H), 8.23 (d, J=6.10 Hz, 1 H), 8.33 (d, J=8.48 Hz, 1 H). MS(DCI-NH₃) [M+H]⁺ at 402.

Example 1042-(3,5-Dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example54F using 1-(3,5-dimethyl-1H-pyrazol-4-yl)ethanone (reference: E. E.Emelina et al., Russ. J. Org. Chem. 1994, 30(10), 1637-1639) for3-acetylpyridine. ¹H NMR (CDCl₃) δ ppm 1.17 (d, J=5.76 Hz, 3 H), 1.51(m, 1 H), 1.80 (m, 2 H), 1.97 (m, 1 H), 2.28 (m, 1 H), 2.44 (m, 2 H),2.51 (s, 3 H), 2.51 (s, 3 H), 3.05 (m, 2H), 3.15 (m, 1 H), 3.32 (m, 1H), 7.47 (d, J=8.48 Hz, 1 H), 7.59 (dd, J=8.48, 2.03 Hz, 1 H), 7.63 (s,1 H), 8.01 (d, J=8.81 Hz, 1 H), 8.10 (d, J=8.81 Hz, 1 H). MS (DCI-NH₃)[M+H]⁺ at 335.

Example 1056-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1H-pyrazol-4-yl)-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(1H-pyrazol-4-yl)-ethanone (reference: G. Heinisch et al.,Monatsh. Chem. 1988, 119, 253-262) for 1-(1,3-thiazol-2-yl)ethanone. ¹HNMR (CDCl₃) δ ppm 1.16 (d, J=6.10 Hz, 3 H), 1.48 (m, 1 H), 1.76 (m, 1H), 1.94 (m, 2H), 2.29 (q, J=8.36 Hz, 1 H), 2.44 (m, 2 H), 3.02 (m, 2H), 3.22 (m, 1 H), 3.38 (m, 1 H), 7.53 (d, J=8.48 Hz, 1 H), 7.56 (s, 1H), 7.57 (dd, 1 H), 7.97 (d, J=7.46 Hz, 1 H), 8.00 (d, J=8.14 Hz, 1 H),8.08 (s, 2 H), 11.14 (br. s, 1 H). MS (DCI-NH₃) [M+H]⁺ at 307.

Example 1062,6-Dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-nicotinamideExample 106A 5-Acetyl-2,6-dimethyl-1,4-dihydro-pyridine-3-carbonitrile

A mixture of 3-aminocrotonitrile (2.0 g, 24 mmol), 2,4-pentanedione (4.9g, 49 mmol), paraformaldehyde (1.5 g, 49 mmol) and piperidine (12 drops)in ethanol (100 mL) was heated to reflux for 4 hours, cooled andconcentrated to dryness. The residue was treated with diethyl ether (150mL). The solid was collected and washed with ether. The solid wastriturated with dichloromethane (2×100 mL). The combined dichloromethanetriturations were concentrated to provide 2.5 g of the title compound.¹H NMR (DMSO-d6) δ ppm 1.92 (t, J=1.02 Hz, 3 H), 2.09 (s, 3 H), 2.10 (s,3 H), 3.20 (s, 2 H), 8.65 (s, 1 H). MS (DCI-NH₃) [M+H]⁺ at 177.

Example 106B 5-acetyl-2,6-dimethylnicotinonitrile

The product from Example 106A (1.0 g, 5.7 mmol) was treated with toluene(15 mL), treated with barium manganate (3.0 g, 12 mmol), stirred overnight at ambient temperature and filtered. The filtrate was concentratedand chromatographed (using 20:1 and then 3:2 hexane:ethyl acetate) toprovide 0.9 g of the title compound. ¹H NMR (CDCl₃) δ ppm 2.60 (s, 3 H),2.79 (s, 3 H), 2.79 (s, 3 H), 8.16 (s, 1 H). MS (DCI-NH₃) [M+H]⁺ at 175.

Example 106C2,6-Dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-nicotinamide

The title compound was prepared using the procedure described in Example57 using 5-acetyl-2,6-dimethylnicotinonitrile for1-(1,3-thiazol-2-yl)ethanone providing the product from Example 67 whicheluted first and the title compound which eluted second. ¹H NMR (CDCl₃)δ ppm 1.18 (d, J=5.43 Hz, 3 H), 1.53 (m, 1 H), 1.80 (m, 2 H), 1.98 (m, 1H), 2.2-2.6 (m, 3 H), 2.65 (s, 3 H), 2.78 (s, 3 H), 3.09 (m, 2 H), 3.19(m, 1 H), 3.33 (m, 1 H), 5.75 (s, 1 H), 5.90 (s, 1 H), 7.52 (d, J=8.48Hz, 1 H), 7.66 (dd, J=8.65, 1.87 Hz, 1 H), 7.71 (s, 1 H), 7.94 (s, 1 H),8.06 (d, J=8.82 Hz, 1 H), 8.19 (d, J=8.14 Hz, 1 H). MS (DCI-NH₃) [M+H]⁺at 389.

Example 1072-[2-(2R-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyridin-4-yl-quinoline

The title compound was prepared using the procedure described in Example51 using 4-pyridinylboronic acid for 3-pyridinylboronic acid. The titlecompound was treated with HCl in ethyl acetate to give the correspondingtrihydrochloride salt. mp 145-147° C. (uncorrected); MS (ESI) 318(M+H)⁺; ¹H NMR (trihydrochloride, CD₃OD, 400 MHz) δ 9.12 (1H, m), 9.03(2H, d), 8.94 (1H, d), 8.65 (2H, d), 8.61 (1H, d), 8.53 (1H, d), 8.12(1H, d), 4.10 (1H, br), 3.90 (1H, br), 3.80 (1H, br), 3.62 (2H, br),3.42 (1H, m), 2.40 (1H, m), 2.3-2.1 (3H, m), 1.82 (1H, br, m), 1.58 (3H,d).

Example 1086-(6-Methoxy-pyridin-3-yl)-2-[2(R)-(2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 6-methoxy-pyridin-3-ylboronic acid for 3-pyridinylboronic acid.

The title compound was treated with L-tartaric acid in IPA to give thecorresponding tartrate. mp 132-134° C. (uncorrected); MS (ESI) 348(M+H)⁺; ¹H NMR (tartrate, DMSO-d₆, 400 MHz) δ 8.62 (1H, d), 8.37 (1H,d), 8.24 (1H, d), 8.18 (1H, dd), 8.08 (1H, dd), 8.04 (1H, d), 7.52 (1H,d), 6.94 (1H, d), 4.05, 3.90 (2H, s), 3.80-3.4 (3H, m), 3.32 (3H, m),3.04 (1H, q), 2.13 (1H, m), 1.90 (2H, m), 1.60 (1H, m), 1.35, 1.03 (3H,d).

Example 1096-(2,6-Difluoro-pyridin-3-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 2,6-difluoro-pyridin-3-ylboronic acid for 3-pyridinylboronicacid. The title compound was treated with L-tartaric acid in IPA to givethe corresponding tartrate. mp 142-143° C. (uncorrected); MS (ESI) 354(M+H)⁺; ¹H NMR (tartrate, DMSO-d₆, 400 MHz) δ 8.62 (1H, q), 8.60 (1H,d), 8.21 (1H, s), 8.08 (1H, d), 7.94 (1H, d), 8.04 (1H, d), 7.59 (1H,d), 7.35 (1H, dd), 4.00 (2H, s), 3.80-3.4 (3H, m), 3.38 (1H, m), 3.25(2H, m), 2.96 (1H, q), 2.12 (1H, m), 1.89 (2H, m), 1.59 (1H, m), 1.32(3H, d).

Example 1106-(6-Chloro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 2-chloro-5-trimethylstannanyl-pyridine for 3-pyridinylboronicacid. The title compound was treated with L-tartaric acid in IPA to givethe corresponding tartrate. mp 167-168° C. (uncorrected); MS (ESI) 352(M+H)⁺; ¹H NMR (tartrate, CD₃OD, 400 MHz) δ 8.87 (1H, d), 8.40 (1H, d),8.05 (1H, d), 8.02 (1H, dd), 8.13 (1H, d), 8.08 (1H, dd), 7.59 (1H, d),7.57 (1H, d), 4.40 (2H, s), 4.05 (1H, br, m), 3.78 (1H, br, m), 3.63(1H, br, m), 3.6-3.4 (3H, m), 3.35 (1H, m), 2.35 (1H, m), 2.14 (2H, m),1.82 (1H, m), 1.58, 1.15 (3H, d).

Example 1116-(2,6-Dichloro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 2,6-dichloro-pyridin-3-ylboronic acid for 3-pyridinylboronicacid. The title compound was treated with HCl in ethyl acetate to givethe corresponding dihydrochloride. mp 105-107° C. (uncorrected); MS(ESI) 386 (M+H)⁺; ¹H NMR (dihydrochloride, DMSO-d₆, 400 MHz) δ 8.52 (1H,d), 8.19 (1H, s), 8.15 (1H, d), 8.10 (1H, d), 7.94 (1H, dd), 7.75 (1H,d), 7.68 (1H, d), 3.90 (2H, br, m), 3.66 (1H, br, m), 3.50 (3H, br, m),3.22 (1H, br, m), 2.22 (1H, br, m), 1.96 (2H, br, m), 1.66 (1H, br, m),1.45 (3H, br, d).

Example 1122-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyrazin-2-yl-quinoline

The title compound was prepared using the procedure described in Example51 using 2-tri-tert-butylstannanyl-pyrazine for 3-pyridinylboronic acid.MS (ESI) 319 (M+H)⁺; ¹H NMR (CDCl₃, 400 MHz) δ 9.20 (1H, d), 8.70 (1H,t), 8.58 (1H, d), 8.50 (1H, d), 8.37 (1H, dd), 8.20 (1H, d), 8.19 (1H,d), 7.43 (1H, d), 3.4-3.2 (4H, m), 2.65 (1H, br, m), 2.45 (1H, br, m),2.34 (1H, br, m), 1.95 (1H, br, m), 1.82 (1H, br, m), 1.75 (1H, br, m),1.50 (1H, br, m), 1.15 (3H, d).

Example 1132-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyrimidin-5-yl-quinoline

The title compound was prepared using the procedure described in Example51 using 5-tri-tert-butylstannanyl-pyrimidine for 3-pyridinylboronicacid. The title compound was treated with HCl in ethyl acetate to givethe corresponding trihydrochloride. mp 160-162° C. (uncorrected); MS(ESI) 319 (M+H)⁺; ¹H NMR (trihydrochloride, DMSO-d₆, 400 MHz) δ 9.32(2H, s), 9.26 (1H, s), 8.70 (1H, d), 8.52 (1H, d), 8.38 (1H, dd), 8.30(1H, d), 7.82 (1H, d), 3.92 (1H, m), 3.65 (3H, br, m), 3.50 (2H, br, m),3.22 (1H, br, m), 2.10 (1H, m), 2.00 (2H, br, m), 1.70 (1H, br, m), 1.50(3H, br, d).

Example 1146-(2,4-Dimethoxy-pyrimidin-5-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 2,6-dimethoxypyrimidin-5-ylboronic acid for 3-pyridinylboronicacid. MS (ESI) 379 (M+H)⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (1H, s), 8.10(1H, d), 8.07 (1H, d), 7.88 (1H, d), 7.82 (1H, dd), 7.38 (1H, d), 4.06(3H, s), 4.05 (3H, s), 3.30 (2H, m), 3.22 (2H, m), 2.60 (1H, m), 2.42(1H, m), 2.30 (1H, q), 1.95 (1H, m), 1.80 (1H, m), 1.72 (1H, m), 1.43(1H, m), 1.13 (3H, d).

Example 115Dimethyl-(4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-amine

The title compound was prepared using the procedure described in Example51 using 4-dimethylaminophenylboronic acid for 3-pyridinylboronic acid.The title compound was treated with L-tartaric acid in IPA to give thecorresponding tartrate. mp 155-156° C. (uncorrected); MS (ESI) 360(M+H)⁺; ¹H NMR (tartrate, DMSO-d₆, 400 MHz) δ 8.30 (1H, d), 8.10 (1H,d), 8.02 (1H, dd), 7.95 (1H, d), 7.68 (2H, d), 7.47 (1H, d), 6.83 (2H,d), 4.00 (2H, s), 3.60 (1H, m), 3.48 (1H, m), 3.27 (2H, m), 3.12 (2H,m), 2.97 (6H, s), 2.82 (1H, m), 2.08 (1H, m), 1.83 (2H, m), 1.52 (1H,m), 1.28 (3H, d).

Example 1161-(4-{2-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-ethanone

The title compound was prepared using the procedure described in Example51 using 4-acetylphenylboronic acid for 3-pyridinylboronic acid. Thetitle compound was treated with L-tartaric acid in IPA to give thecorresponding tartrate. mp 152-154° C. (uncorrected); MS (ESI) 359(M+H)⁺; ¹H NMR (tartrate, CD3OD, 400 MHz) δ 8.40 (1H, d), 8.24 (1H, s),8.11 (2H, d), 8.09 (2H, m), 7.92 (2H, d), 7.55 (1H, d), 4.39 (2H, s),4.01 (1H, m), 3.79 (1H, m), 3.63 (1H, m), 3.53 (1H, m), 3.50 (2H, m),3.31 (1H, m), 2.64 (3H, s), 2.38 (1H, m), 2.12 (2H, m), 1.82 (1H, m),1.58 (3H, d).

Example 1176-(4-Chloro-phenyl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 4-chlorophenylboronic acid for 3-pyridinylboronic acid. Thetitle compound was treated with HCl in ethyl acetate to give thecorresponding dihydrochloride. mp 154-155° C. (uncorrected); MS (ESI)351 (M+H)⁺; ¹H NMR (dihydrochloride, DMSO-d₆, 400 MHz) δ 8.70 (1H, d),8.43 (1H, s), 8.27 (2H, s), 7.90 (2H, d), 7.81 (1H, d), 7.60 (2H, d),3.90 (1H, br, m), 3.63 (3H, br, m), 3.50 (2H, br, m), 3.23 (1H, br, m),2.20 (1H, s), 2.00 (2H, m), 1.68 (1H, m), 1.42 (3H, br, d).

Example 1186-(2,6-Dimethyl-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridinefor 3-pyridinylboronic acid. The title compound was treated with HCl inethyl acetate to give the corresponding trihydrochloride. mp 176-177° C.(uncorrected); MS (ESI) 346 (M+H)⁺; ¹H NMR (trihydrochloride, CD₃OD, 400MHz) δ 9.08 (1H, d), 8.46 (2H, d), 8.42 (1H, d), 8.18 (1H, dd), 8.14(1H, d), 7.89 (1H, d), 4.08 (1H, m), 3.90 (1H, m), 3.82 (2H, m), 3.65(2H, br, m), 3.42 (1H, m), 2.87 (3H, s), 2.75 (3H, s), 2.39 (1H, m),2.18 (2H, br, m), 1.83 (1H, br, m), 1.58 (3H, d).

Example 1196-(5-Methoxy-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for3-pyridinylboronic acid. MS (ESI) 348 (M+H)⁺; ¹H NMR (CDCl₃, 400 MHz) δ8.57 (1H, s), 8.34 (1H, d), 8.12 (2H, d), 7.96 (1H, d), 7.90 (1H, dd),7.48 (1H, dd), 7.40 (1H, d), 3.95 (3H, s), 3.76, 3.63 (1H, m), 3.4-3.2(3H, m), 2.64 (1H, m), 2.45 (1H, m), 2.32 (1H, q), 1.95 (1H, m), 1.82(1H, m), 1.73 (1H, m), 1.45 (1H, m), 1.15 (3H, d).

Example 1206-(3,5-Dimethyl-isoxazol-4-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using 3,5-dimethyl-isoxazol-4-ylboronic acid for 3-pyridinylboronicacid. The title compound was treated with HCl in ethyl acetate to givethe corresponding trihydrochloride. mp 174-175° C. (uncorrected); MS(ESI) 336 (M+H)⁺; ¹H NMR (trihydrochloride, DMSO-d₆, 400 MHz) δ 8.72(1H, d), 8.30 (1H, d), 8.18 (1H, d), 7.97 (1H, dd), 7.83 (1H, d), 3.90(1H, br, m), 3.65 (2H, br, m), 3.52 (2H, br, m), 3.23 (1H, br, m), 2.50(3H, s), 2.32 (3H, s), 2.20 (2H, br, m), 2.00 (2H, br, m), 1.70 (1H, br,m), 1.45 (3H, br, d).

Example 1214-{2-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-benzoic acidmethyl ester

The title compound was prepared using the procedure described in Example51 using 4-methoxycarbonylphenylboronic acid for 3-pyridinylboronicacid. The title compound was treated with HCl in ethyl acetate to givethe corresponding dihydrochloride. mp 172-174° C. (uncorrected); MS(ESI) 375 (M+H)⁺; ¹H NMR (dihydrochloride, DMSO-d₆, 400 MHz) δ 8.86 (1H,d), 8.60 (1H, s), 8.39 (2H, s), 8.12 (2H, d), 8.04 (2H, d), 7.95 (1H,d), 3.95 (1H, br, m), 3.90 (3H, s), 3.70 (2H, br, m), 3.52 (2H, br, m),3.24 (1H, br, m), 2.20 (2H, m), 2.00 (2H, br, m), 1.68 (1H, br, m), 1.45(3H, br, d).

Example 1222-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-6-(4-methylsulfanyl-phenyl)-quinoline

The title compound was prepared using the procedure described in Example51 using 4-methylsulfanylphenylboronic acid for 3-pyridinylboronic acid.

The title compound was treated with HCl in ethyl acetate to give thecorresponding dihydrochloride. mp 158-159° C. (uncorrected); MS (ESI)363 (M+H)⁺; ¹H NMR (dihydrochloride, DMSO-d₆, 400 MHz) δ 8.79 (1H, d),8.43 (1H, s), 8.31 (2H, br, s), 7.88 (1H, d), 8.02 (2H, d), 7.43 (2H,d), 3.95 (1H, br, m), 3.67 (2H, br, m), 3.50 (3H, br, m), 3.23 (1H, br,m), 2.53 (3H, s), 2.20 (1H, m), 2.00 (2H, br, m), 1.68 (1H, br, m), 1.45(3H, br, d).

Example 1236-(6-Fluoro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described in Example51 using2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for3-pyridinylboronic acid. The title compound was treated with HCl inethyl acetate to give the corresponding trihydrochloride. mp 162-163° C.(uncorrected); MS (ESI) 336 (M+H)⁺; ¹H NMR (trihydrochloride, DMSO-d₆,400 MHz) δ 8.93 (1H, d), 8.77 (1H, d), 8.58 (1H, d), 8.50 (1H, td), 8.40(2H, m), 7.96 (1H, d), 7.40 (1H, dd), 3.95 (1H, br, m), 3.71 (2H, br,m), 3.52 (2H, br, m), 3.24 (1H, br, m), 3.05 (1H, m), 2.20 (1H, m), 2.00(2H, br, m), 1.68 (1H, br, m), 1.45 (3H, br, d).

Example 1245-{2-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-nicotinonitrile

The title compound was prepared using the procedure described in Example51 using5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile for3-pyridinylboronic acid. The title compound was treated with L-tartaricacid in IPA to give the corresponding tartrate. mp 100-102° C.; MS (ESI)343 (M+H)⁺; ¹H NMR (tartrate, DMSO-d₆, 400 MHz) δ 9.36 (1H, d), 9.05(1H, d), 8.81 (1H, dd), 8.49 (1H, d), 8.37 (1H, d), 8.20 (1H, dd), 8.09(1H, d), 7.59 (1H, d), 4.04 (2H, s), 3.65 (1H, m), 3.49 (1H, m), 3.36(2H, m), 3.17 (2H, m), 2.89 (1H, m), 2.09 (1H, m), 1.88 (2H, br, m),1.56 (1H, br, m), 1.28, 1.05 (3H, d).

Example 1252,4-Dimethoxy-5-{6-[2-((2R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidineExample 125A2-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-naphthalen-2-yl]-ethanol

A mixture of the product from Example 1E (0.1020 g, 0.41 mmol),2,4-dimethoxypyrimidin-5-yl-boronic acid (0.0920 g, 0.50 mmol),dichlorobis (triphenylphosphine)-palladium (II) (0.0096 g, 0.014 mmol),and K₃PO₄.H₂O in isopropyl alcohol (5 mL) and H₂O (2 mL) was stirred at65° C. for 2 hours. The reaction mixture was cooled to room temperaturethen concentrated under reduced pressure. The residue was partitionedbetween brine and ethyl acetate. The aqueous layer was washed with ethylacetate, and the combined organic extracts were dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (7:3 hexane/ethylacetate). Fractions containing product were combined to provide (0.0376g, 30% yield). ¹H NMR (CDCl₃, 300 MHz), δ 8.37 (s, 1H), 7.95 (s, 1H),7.86-7.82 (d, J=6 Hz, 2H), 7.71 (s, 1H), 7.64-7.59 (d, J=9 Hz, 1H),7.46-7.6 (s, J=9 Hz, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.89-3.84 (t,J=7.5 Hz, 2H), 3.30-2.98 (t, J=7.5 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 311.

Example 125B Methanesulfonic acid2-[6-(2,4-dimethoxy-pyrimidin-5-yl)-naphthalen-2-yl]-ethyl ester

The compound was prepared by the method in Example 3B, using2-[6-(2,4-dimethoxy-pyrimidin-5-yl)-naphthalen-2-yl]-ethanol for1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone (39 mg, 84% yield).¹H NMR (CD₃OD, 300 MHz), δ 8.38 (s, 1H), 7.98 (s, 1H), 7.9-7.86 (d, J=9Hz, 2H), 7.7 (s, 1H), 7.66-7.61 (d, J=6 Hz, 1H), 7.49-7.44 (d, J=6 Hz,1H), 4.57-4.52 (t, J=7.5 Hz, 2H), 4.08 (s, 3H), 4.06 (s, 3H), 3.27-3.19(t, J=7.5 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 389.

Example 125C2,4-Dimethoxy-5-{6-[2-((2R)-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine

The title compound was prepared by the method in Example 3C using,methanesulfonic acid2-[6-(2,4-dimethoxy-pyrimidin-5-yl)-napthalen-2-yl]-ethyl ester for2-[6-(3-acetylphenyl)-2-naphthyl]ethyl methanesulfonate (0.0063 g, 14%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.38 (s, 1H), 7.98 (s, 1H), 7.9-7.86(d, J=9 Hz, 2H), 7.7 (s, 1H), 7.66-7.61 (d, J=6 Hz, 1H), 7.49-7.44 (d,J=6 Hz, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.18-3.11 (m, 2H), 3.09-2.96(m, 2H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H),1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 378.

Example 1262,6-Difluoro-3-{6-[2((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridineExample 126A 2-[6-(2,6-Difluoro-pyridin-3-yl)-naphthalen-2-yl]-ethanol

The compound was prepared by the method in Example 125A using2,6-difluoropyrid-3-yl-boronic acid for2,4-dimethoxypyrimidin-5-yl-boronic acid (23 mg, 20% yield). ¹H NMR(CD₃OD, 300 MHz), δ 8.32-8.25 (m, 1H), 8.04, (s, 1H), 7.91-7.87 (m, 2H),7.74, (s, 1H), 7.67-7.62 (d, J=6 Hz, 1H), 7.48-7.45 (d, J=6.6 Hz, 1H),7.15-7.1 (d, J=5.4 Hz, 1H), 3.92-3.85 (t, J=6 Hz, 2H), 3.06-2.99 (t, J=6Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 286.

Example 126B Methanesulfonic acid2-[6-(2,6-difluoro-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester

The compound was prepared using the method in Example 3B using,2-[6-(2,6-difluoro-pyridin-3-yl)-naphthalen-2-yl]-ethanol for1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone (24 mg, 82% yield).¹H NMR (CD₃OD, 300 MHz), δ 8.34-8.25 (m, 1H), 8.05 (s, 1H), 7.97-7.9 (m,2H), 7.82 (s, 1H), 7.72-7.67 (d, J=6 Hz, 1H), 7.54-7.48 (d, J=7.8 Hz,1H), 7.17-7.11 (d, J=6 Hz, 1H), 4.57-4.52 (t, J=6 Hz, 2H), 4.15-4.06 (t,J=6 Hz, 2H), 2.94 (s, 3H). MS (DCI-NH₃) [M+NH₄]⁺ at 381.

Example 126C2,6-Difluoro-3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine

The title compound was prepared using the method in Example 3C using,methanesulfonic acid2-[6-(2,6-difluoro-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester for2-[6-(3-acetylphenyl)-2-naphthyl]ethyl methanesulfonate. ¹H NMR (CD₃OD,300 MHz), δ 8.34-8.25 (m, 1H), 8.05 (s, 1H), 7.97-7.9 (m, 2H), 7.82 (s,1H), 7.72-7.67 (d, J=6 Hz, 1H), 7.54-7.48 (d, J=7.8 Hz, 1H), 7.17-7.11(d, J=6 Hz, 1H), 3.18-3.11 (m, 2H), 3.09-2.96 (m, 2H), 2.51-2.4 (m, 2H),2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.4 (m,1H), 1.15 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 353.

Example 127Cyclopropyl-(3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-phenyl)-methanoneExample 127A (3-Bromo-phenyl)-cyclopropyl-methanone

A mixture of 1-(3-bromo-phenyl)-4-chloro-1-oxo-butane (1.0 g, 3.82 mmol)and a 1.0 M solution of sodium bis(trimethylsilyl)amide (4.21 mL, 4.21mmol, 1.1 equiv.) in toluene (10 mL) was stirred at room temperature for3 h. The reaction mixture was concentrated under reduced pressure andthe residue was partitioned between ethyl acetate and brine. The organiclayer was dried (MgSO₄), and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by columnchromatography (98:2 hexane/ethyl acetate) to provide the titleintermediate (0.53 g, 62% yield). ¹H NMR (CDCl3, 300 MHz), δ 8.14 (t,J=1.7 Hz, 1H) 7.95-7.92 (m, 1H), 7.71-7.67 (m, 1H), 7.36 (t, J=7.8 Hz,1H), 2.66-2.58 (m, 1H), 1.29-1.24 (m, 2H), 1.11-1.05 (m, 2H). MS(DCI-NH₃) [M+H]⁺ at 225.

Example 127B(3-{6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-naphthalen-2-yl}-phenyl)-cyclopropyl-methanone

The compound was prepared using the method in 26C substituting(3-bromo-phenyl)-cyclopropyl-methanone in place of 5-bromopyrimidine (71mg, 61% yield). ¹H NMR (CDCl₃, 300 MHz), δ 8.35 (s, 1H) 8.09-8.02 (m,2H), 7.94-7.87 (m, 3H), 7.79-7.71 (m, 2H), 7.83-7.58 (t, J=8.1 Hz, 1H),7.45-7.4 (d, J=7.5 Hz, 1H), 4.03-3.96 (q, J=6 Hz, 2H), 3.1-3.04 (t, J=6Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 (m, 2H), 1.15-1.08 (m, 2H), 0.87(s, 9H), −0.02 (s, 3H). MS (DCI-NH₃) [M+H]⁺ at 431.

Example 127Ccyclopropyl-{3-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-phenyl}-methanone

The compound was prepared by the method in 26D using(3-{6-[tert-butyl-dimethyl-silanyloxy)-ethyl]-naphthalen-2-yl}-phenyl)-cyclopropyl-methanonefor 5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine(71 mg, 61% yield). ¹H NMR (CDCl₃, 300 MHz), δ 8.35 (s, 1H) 8.09-8.02(m, 2H), 7.94-7.87 (m, 3H), 7.79-7.71 (m, 2H), 7.83-7.58 (t, J=8.1 Hz,1H), 7.45-7.4 (d, J=7.5 Hz, 1H), 4.03-3.96 (q, J=6 Hz, 2H), 3.1-3.04 (t,J=6 Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 (m, 2H), 1.15-1.08 (m, 2H). MS(DCI-NH₃) [M+H]⁺ at 317.

Example 127D Methanesulfonic acid2-[6-(3-cyclopropanecarbonyl-phenyl)-naphthalen-2-yl]-ethyl ester

The compound was prepared using the method in 3B usingcyclopropyl-{3-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-phenyl}-methanonefor 1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone (68 mg, 76%yield). ¹H NMR (CDCl₃, 300 MHz), δ 8.35 (s, 1H) 8.09-8.02 (m, 2H),7.94-7.87 (m, 3H), 7.79-7.71 (m, 2H), 7.83-7.58 (t, J=8.1 Hz, 1H),7.45-7.4 (d, J=7.5 Hz, 1H), 4.1-4.05 (t, J=6 Hz, 2H), 3.6 (s, 3H),3.17-3.02 (t, J=6 Hz, 2H), 2.71-2.69 (m, 1H), 1.35-1.28 (m, 2H),1.15-1.08 (m, 2H). MS (DCI-NH₃) [M+NH₄]⁺ at 412.

Example 127ECyclopropyl-(3-{6-[2-((2R)2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-phenyl)-methanone

The title compound was prepared using the method in 3C using methanesulfonic acid2-[6-(3-cyclopropanecarbonyl-phenyl)-naphthalen-2-yl]-ethyl ester for2-[6-(3-acetylphenyl)-2-naphthyl]ethyl methanesulfonate (3.9 mg, 6%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.35 (s, 1H) 8.09-8.02 (m, 2H),7.94-7.87 (m, 3H), 7.79-7.71 (m, 2H), 7.83-7.58 (t, J=8.1 Hz, 1H),7.45-7.4 (d, J=7.5 Hz, 1H), 3.29-3.18 (m, 1H), 3.09-2.91 (m, 3H),2.6-2.39 (m, 3H), 2.1-1.98 (m, 1H), 2.9-2.77 (m, 1H), 2.58-2.42 (m, 1H),1.35-1.32 (m, 2H), 1.22-1.12 (m, 6H), 1.96-1.83 (m, 1H). MS (DCI-NH₃)[M+H]⁺ at 384.

Example 1283-Methoxy-6-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazineExample 128A3-{6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-naphthalen-2-yl}-6-methoxy-pyridazine

The compound was prepared using the method in 26C using3-chloro-6-methoxy-pyridazine for 5-bromopyrimidine (64 mg, 76% yield).¹H NMR (CDCl₃, 300 MHz), δ 8.43 (s, 1H), 8.24-8.2 (d, J=7.5 Hz, 1H),7.96-7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J=6 Hz, 1H), 7.12-7.07(d, J=9 Hz, 1H), 4.96-4.86 (m, 2H), 4.22 (s, 3H), 3.03-2.91 (m, 2H),0.87 (s, 9H), −0.02 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at 395.

Example 128B 2-[6-(6-Methoxy-pyridazin-3-yl)-naphthalen-2-yl]-ethanol

The compound was prepared by the method in 26D using3-[6-[2(tert-butyl-dimethyl-silanyloxy)-ethyl]-naphthalen-2-yl}-6-methoxy-pyridazinefor 5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine(6.7 mg, 37% yield). ¹H NMR (CDCl₃, 300 MHz), δ 8.43 (s, 1H), 8.24-8.2(d, J=7.5 Hz, 1H), 7.96-7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J=6Hz, 1H), 7.12-7.07 (d, J=9 Hz, 1H), 4.22 (s, 3H), 4.03 (q, J=5.4 Hz,2H), 3.09-3.04 (d, J=5.4 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 281.

Example 128C Methanesulfonic acid2-[6-(6-methoxy-pyridazin-3-yl)-naphthalen-2-yl]-ethyl ester

The compound was prepared by the method in Example 3B using2-[6-(6-methoxy-pyridazin-3-yl)-naphthalen-2-yl]-ethanol for1-{3-[6-(2-hydroxyethyl)-2-naphthyl]phenyl}ethanone (14 mg, 64% yield).¹H NMR (CDCl₃, 300 MHz), δ 8.43 (s, 1H), 8.24-8.2 (d, J=7.5 Hz, 1H),7.96-7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J=6 Hz, 1H), 7.12-7.07(d, J=9 Hz, 1H), 4.57-4.52 (t, J=6 Hz, 2H), 4.22 (s, 3H), 4.15-4.06 (t,J=6 Hz, 2H) 2.94 (s, 3H). MS (DCI-NH₃) [M+NH₄]⁺ at 359.

Example 128D3-Methoxy-6-{6-[2-((2R)2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazine

The title compound was prepared using the method in 1H usingmethanesulfonic acid2-[6-(6-methoxy-pyridazin-3-yl)-naphthalen-2-yl]-ethyl ester for2-[6-(4-cyanophenyl)-2-naphthyl]ethyl 4-methylbenzenesulfonate (3 mg,22% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.43 (s, 1H), 8.24-8.2 (d, J=7.5Hz, 1H), 7.96-7.81 (m, 3H), 7.63 (s, 1H), 7.44-7.41 (d, J=6 Hz, 1H),7.12-7.07 (d, J=9 Hz, 1H), 4.17 (s, 3H), 3.18-3.11 (m, 2H), 3.09-2.96(m, 2H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H),1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+NH₄]⁺ at 348.

Example 1294-{6-[2-(2-Methyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile

The title compound was prepared by the method described in Example 1Husing 2-methylpiperidine in place of (2R)-2-methylpyrrolidine (9 mg,8.4% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.17 (s, 1H), 7.97-7.91 (m, 4H),7.87-7.75 (m, 4H), 7.45 (d, J=6 Hz, 1H), 3.13-2.86 (m, 5H), 2.55-2.49(m, 2H), 1.81-1.67 (m, 4H), 1.46-1.33 (m, 2H), 1.08 (d, J=6 Hz, 3H). MS(DCI-NH₃) [M+H]+ at 355.

Example 1304-{6-[2-((2R)-2-Ethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-benzonitrile

The title compound was prepared by the method in 1H using(2R)-2-ethylpyrrolidine for (2R)-2-methylpyrrolidine (13 mg, 7.5%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.17 (s, 1H), 7.97-7.91 (m, 4H),7.87-7.75 (m, 4H), 7.45 (d, J=6 Hz, 1H), 3.29-3.17 (m, 2H), 3.19-2.95(m, 2H), 2.49-2.42 (m, 2H), 2.41-2.31 (m, 1H), 2.14-1.99 (m, 1H),1.89-1.78 (m, 2H), 1.63-1.42 (m, 2H), 1.31-1.2 (m, 1H), 0.99-0.89 (m,3H). MS (DCI-NH₃) [M+H]⁺ at 355.

Example 1312-{6-[2-((2S)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (2S)-2-methylpyrrolidine in place of(2R)-2-methylpyrrolidine (42 mg, 30% yield). ¹H NMR (HCl salt, CD₃OD,300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H),7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H),3.32-3.20 (m, 2H), 3.16-2.99 (m, 2H), 3.83-3.51 (m, 3H), 2.17-2.02 (m,1H), 1.95-1.82 (m, 2H), 1.52-1.48 (m, 1H), 1.23 (d, J=2 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 334.

Example 1322-[6-(2-Piperidin-1-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting piperidine in place of (2R)-2-methylpyrrolidine (42 mg, 50%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H),7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12Hz, 1H), 3.1-3.0 (m, 2H), 2.84-2.75 (m, 2H), 2.63-2.58 (m, 4H) 1.74-1.60(m, 4H), 1.60-1.51 (m, 2H). MS (DCI-NH₃) [M+H]⁺ at 334.

Example 1332-{6-[2-(tert-Butyl-methyl-amino)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting methyl(t-butyl)amine in place of (2R)-2-methylpyrrolidine(26 mg, 31% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H),7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H),7.15 (dd, J=2, 12 Hz, 1H), 3.1 (s, 3H), 3.01-2.9 (m, 4H), 1.23 (s, 9H).MS (DCI-NH₃) [M+H]⁺ at 336.

Example 1342-[6-(2-Diethylamino-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting diethylamine in place of (2R)-2-methylpyrrolidine (11 mg,14% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m,2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2,12 Hz, 1H), 3.1 (m, 4H), 3.0-2.91 (m, 4H), 1.26-1.19 (m, 6H). MS(DCI-NH₃) [M+H]⁺ at 322.

Example 1352-[6-(2-Morpholin-4-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting morpholine in place of (2R)-2-methylpyrrolidine (27 mg, 34%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H),7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12Hz, 1H), 3.75-3.69 (m, 2H), 3.69-3.62 (m, 1H), 3.61-3.49 (m, 1H),3.06-2.99 (m, 2H), 2.75-2.71 (m, 2H), 2.61-2.58 (m, 4H). MS (DCI-NH₃)[M+H]⁺ at 336.

Example 1362-{6-[2-(Ethyl-methyl-amino)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31H usingethylmethylamine for (2R)-2-methylpyrrolidine (30 mg, 37% yield). ¹H NMR(CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H),7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H),3.07-2.98 (m, 2H), 2.85-2.77 (m, 2H), 2.69-2.6 (m, 2H), 2.41 (s, 3H),1.17 (t, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 308.

The title compound was prepared by the method in Example 31Hsubstituting (S)-2-fluoromethylpyrrolidine in place of(2R)-2-methylpyrrolidine (21 mg, 24% yield). ¹H NMR (CD₃OD, 300 MHz), δ8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H),7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 4.58-4.51 (m, 2H),4.48-4.29 (d, J=36 Hz, 1H), 3.33-3.21 (m, 2H), 3.06-2.99 (m, 2H),2.8-2.71 (m, 1H), 2.54-2.42 (m, 1H), 2.02-1.95 (m, 1H), 1.88-1.79 (m,1H), 1.71-1.59 (m, 1H), 1.33-1.29 (m, 1H). MS (DCI-NH₃) [M+H]⁺ at 352.

Example 1382-{6-[2-((2S)-2-Hydroxymethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (S)-prolinol in place of (2R)-2-methylpyrrolidine (67 mg,32% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m,2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2,12 Hz, 1H), 3.66 (m, 2H), 3.17-3.0 (m, 3H), 2.99-2.93 (m, 1H), 2.79-2.73(m, 1H), 2.11-2.02 (m, 1H), 1.97-1.82 (m, 3H), 1.8-1.72 (m, 1H). MS(DCI-NH₃) [M+H]⁺ at 350.

Example 1392-{6-[2-((R)-2-Ethyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (2R)-2-ethylpyrrolidine in place of(2R)-2-methylpyrrolidine (3.1 mg, 5.7% yield). ¹H NMR (CD₃OD, 300 MHz),δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H),7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 3.29-3.17 (m, 2H),3.19-2.95 (m, 2H), 2.49-2.42 (m, 2H), 2.41-2.31 (m, 1H), 2.14-1.99 (m,1H), 1.89-1.78 (m, 2H), 1.63-1.42 (m, 2H), 1.31-1.2 (m, 1H), 0.99-0.89(m, 3H). MS (DCI-NH₃) [M+H]⁺ at 348.

Example 1402-[6-(2-Azetidin-1-yl-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting azetidine in place of (2R)-2-methylpyrrolidine (1.3 mg,2.5% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m,2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2,12 Hz, 1H), 3.44-3.2 (m, 6H), 1.36-1.29 (m, 2H), 1.18-1.23 (d, J=4.5 Hz,2H). MS (DCI-NH₃) [M+H]⁺ at 306.

Example 1412-{6-[2-((2S)-2-Fluoromethyl-azetidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (2S)-2-fluoromethylazetidine in place of(2R)-2-methylpyrrolidine (1.7 mg, 3.4% yield). ¹H NMR (CD₃OD, 300 MHz),δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H),7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 3.24-2.8 (m, 5H),2.76-2.62 (m, 1H), 2.09-1.93 (m, 1H), 1.68-1.53 (m, 1H), 1.3-1.2 (m,2H), 0.98-0.91 (m, 1H). MS (DCI-NH₃) [M+H]⁺ at 337.

Example 1422-{6-[2-((2S)-2-Hydroxymethyl-azetidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31H using(2S)-2-hydroxymethylazetidine for (2R)-2-methylpyrrolidine (2 mg, 3.7%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H),7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12Hz, 1H), 4.08-3.98 (m, 1H), 4.0-3.73 (m, 3H), 3.55-3.45 (m, 1H),3.42-3.34 (m, 1H), 3.24-3.14 (m, 1H), 3.09-2.98 (m, 2H), 2.33-2.98 (m,2H), 1.34-1.22 (m, 1H). MS (DCI-NH₃) [M+H]⁺ at 336.

Example 1432-{6-[2-((2R,5R)-2,5-Dimethyl-pyrrolidin-1-yl)-ethyl]naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31H using(2R,5R)-2,5-dimethylpyrrolidine for (2R)-2-methylpyrrolidine (2 mg, 3.7%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H),7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12Hz, 1H), 3.51-3.49 (m, 1H), 3.15-3.05 (m, 1H), 2.39-2.28 (m, 4H),1.86-1.76 (m, 4H), 1.39-1.46 (d, J=5.1 Hz, 6H). MS (DCI-NH₃) [M+H]⁺ at348.

Example 1442-{6-[2-((2R,6S)-2,6-Dimethyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (2R,6S)-2,6-dimethylpiperidine in place of(2R)-2-methylpyrrolidine (1.2 mg, 2.4% yield). ¹H NMR (CD₃OD, 300 MHz),δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H),7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 3.61-3.18 (m, 7H),2.1-1.91 (m, 1H), 1.9-1.84 (m, 1H), 1.74-1.58 (m, 3H) 1.5-1.44 (d, J=3.6Hz, 6H). MS (DCI-NH₃) [M+H]⁺ at 362.

Example 1452-{6-[2-((R)-3-Hydroxy-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (3R)-3-hydroxypiperidine in place of(2R)-2-methylpyrrolidine (1.3 mg, 2.8% yield). ¹H NMR (CD₃OD, 300 MHz),δ 8.12-8.06 (m, 2H), 7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H),7.55-7.46 (m, 2H), 7.15 (dd, J=2, 12 Hz, 1H), 3.78-3.67 (m, 1H),3.1-2.99 (m, 3H), 2.91-2.81 (m, 1H), 2.8-2.72 (m, 2H), 2.22-2.01 (m,1H), 1.99-1.89 (m, 1H), 1.86-1.78 (m, 1H), 1.69-1.54 (m, 1H), 1.36-1.22(m, 1H). MS (DCI-NH₃) [M+H]⁺ at 350.

Example 1462-{6-[2-((R)-2-Methyl-piperidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one

The title compound was prepared by the method in Example 31Hsubstituting (R)-2-methylpiperidine in place of (2R)-2-methylpyrrolidine(9.2 mg, 1.8% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.12-8.06 (m, 2H),7.97-7.89 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 1H), 7.55-7.46 (m, 2H),7.15 (dd, J=2, 12 Hz, 1H), 3.14-2.88 (m, 5H), 2.66-2.49 (m, 2H),1.8-1.56 (m, 4H), 1.46-1.34 (m, 2H), 1.22-1.19 (d, J=4.8 Hz, 3H). MS(DCI-NH₃) [M+H]⁺ at 348.

Example 1472,6-Dimethyl-3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridineExample 147A 2-[6-(2,6-Dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethanol

The compound was prepared by the method in Example 1F substituting2,6-dimethylpyridyl-3-boronic acid in place of para-cyanophenyl boronicacid (78 mg, 35% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.09-8.05 (m, 1H),7.99-7.87 (m, 2H), 7.82-7.79 (m, 1H), 7.66-7.62 (m, 1H), 7.53-7.44 (m,2H), 7.22-7.13 (m, 1H), 4.84-4.51 (t, J=6 Hz, 2H), 3.05-2.98 (t, J=6 Hz,2H), 2.56 (s, 3H), 2.06 (s, 3H). MS (DCI-NH₃) [M+H]⁺ at 278.

Example 147B Methanesulfonic acid2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester

The compound was prepared by the method in Example 3B substituting2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethanol in place of4-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-benzonitrile (0.9763 g, 97%yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.09-8.05 (m, 1H), 7.99-7.87 (m, 2H),7.82-7.79 (m, 1H), 7.66-7.62 (m, 1H), 7.53-7.44 (m, 2H), 7.22-7.13 (m,1H), 4.57-4.52 (t, J=7.5 Hz, 2H), 4.08 (s, 3H), 3.27-3.19 (t, J=7.5 Hz,2H). MS (DCI-NH₃) [M+H]⁺ at 356.

Example 147C2,6-Dimethyl-3-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine

The title compound was prepared by the method in Example 3C substitutingmethanesulfonic acid2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester in placeof methanesulfonic acid 2-[6-(4-cyano-phenyl)-naththalen-2-yl]-ethylester (12 mg, 12% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.09-8.05 (m, 1H),7.99-7.87 (m, 2H), 7.82-7.79 (m, 1H), 7.66-7.62 (m, 1H), 7.53-7.44 (m,2H), 7.22-7.13 (m, 1H), 4.08 (s, 3H), 4.06 (s, 1H), 3.18-3.11 (m, 2H),3.09-2.96 (m, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.51-2.4 (m, 2H),2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.4 (m,1H), 1.15 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 345.

Example 1485-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-thiazoleExample 148A 2-(6-Thiazol-5-yl-naphthalen-2-yl)-ethanol

A mixture of the product from Example 1E (206 mg, 0.82 mmol),2-trimethylsilyl-5-tributylylin-thiazole (369 mg, 0.82 mmol),dichlorobis-(triphenylphosphine)-palladium (II) (30 mg, 0.43 mmol), andlithium chloride (123 mg, 2.9 mmol), were stirred at 100° C. in 25 mLtoluene overnight. The reaction was cooled to room temperature thendiluted with 5 mL aqueous KF. The aq. layer was extracted with ethylacetate. The organic layer was dried over MgSO₄ and solid was removed byfiltration. The resulting brown oil was purified by columnchromatography 1:1 hexane/ethyl acetate (0.081 g, 39% yield). ¹H NMR(CCl₃D, 300 MHz), δ 8.84 (s, 1H), 8.16 (s, 1H), 8.0 (s, 1H), 7.89-7.82(m, 2H), 7.71-7.66 (m, 2H), 7.45-7.4 (m, 1H), 4.1-3.94 (t, J=5.7 Hz,2H), 3.09-3.02 (t, J=5.7 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 256.

Example 148B Methanesulfonic acid2-(6-thiazol-5-yl-naphthalen-2-yl)-ethyl ester

The compound was prepared by the method in Example 3B substituting2-(6-thiazol-5-yl-naphthalen-2-yl)-ethanol in place of4-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-benzonitrile (91 mg, 86% yield).¹H NMR (CCl₃D, 300 MHz), δ 8.84 (s, 1H), 8.16 (s, 1H), 8.0 (s, 1H),7.89-7.82 (m, 2H), 7.71-7.66 (m, 2H), 7.45-7.4 (m, 1H), 4.57-4.52 (t,J=7.5 Hz, 2H), 4.08 (s, 3H), 3.27-3.19 (t, J=7.5 Hz, 2H). MS (DCI-NH₃)[M+H]⁺ at 334.

Example 148C5-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-thiazole

The title compound was prepared by the method in Example 3C substitutingmethanesulfonic acid 2-(6-thiazol-5-yl-naphthalen-2-yl)-ethyl ester inplace of methanesulfonic acid2-[6-(4-cyano-phenyl)-naththalen-2-yl]-ethyl ester (53 mg, 50% yield).¹H NMR (CD₃OD, 300 MHz), δ 8.84 (s, 1H), 8.16 (s, 1H), 8.0 (s, 1H),7.89-7.82 (m, 2H), 7.71-7.66 (m, 2H), 7.45-7.4 (m, 1H), 4.08 (s, 3H),4.06 (s, 1H), 3.18-3.11 (m, 2H), 3.09-2.96 (m, 2H), 2.55 (s, 3H), 2.45(s, 3H), 2.51-2.4 (m, 2H), 2.39-2.31 (m, 1H), 2.10-1.91 (m, 1H),1.89-1.76 (m, 2H), 1.55-1.4 (m, 1H), 1.15 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 323.

Example 1492-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidineExample 149A2-[6-(tert-Butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-pyrimidine

The compound was prepared by the method in Example 26C substituting2-bromopyrimidine in place of 5-bromopyrimidine (157 mg, 60% yield), 1HNMR (CD₃OD, 300 MHz), δ 8.95 (s, 1H), 8.92-8.89 (m, 2H), 8.54-8.51 (m,1H), 8.07-7.94 (m, 3H), 7.55-7.51 (m, 1H), 7.42-7.38 (m, 1H), 4.96-4.86(m, 2H), 3.03-2.91 (m, 2H), 0.87 (s, 9H), −0.02 (s, 6H). MS (DCI-NH₃)[M+H]⁺ at 365.

Example 149B (6-Pyrimidin-2-yl-naphthalen-2-yl)-ethanol

The compound was prepared by the method in Example 26D substituting2[6-[tert-butyl-dimethyl-silanyloxy]ethylynaphthalen-2-yl]-pyrimidine inplace of5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]-pyrimidine(56 mg, 72% yield. ¹H NMR (CD₃OD, 300 MHz), δ 8.95 (s, 1H), 8.92-8.89(m, 2H), 8.54-8.51 (m, 1H), 8.07-7.94 (m, 3H), 7.55-7.51 (m, 1H),7.42-7.38 (m, 1H), 4.1-3.94 (t, J=5.7 Hz, 2H), 3.09-3.02 (t, J=5.7 Hz,2H). MS (DCI-NH₃) [M+H]⁺ at 237.

Example 149C Methanesulfonic acid2-(6-pyrimidin-2-yl-naphthalen-2-yl)-ethyl ester

The title compound was prepared by the method of Example 3B, using theproduct from Example 149B in place of the product from Example 3A togive an off-white solid.

Example 149D2-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidine

The title compound was prepared by the method of Example 3C using theproduct from Example 149C in place of the product from Example 3B (56mg, 41% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.95 (s, 1H), 8.92-8.89 (m,2H), 8.54-8.51 (m, 1H), 8.07-7.94 (m, 3H), 7.55-7.51 (m, 1H), 7.42-7.38(m, 1H), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1H), 2.75-2.55 (m, 3H),2.45-2.34 (m, 2H), 2.09-1.98 (m, 1H), 1.91-1.78 (m, 2H), 1.56-1.41 (m,1H), 1.19 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 318.

Example 1503-Chloro-6-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazineExample 150A3-[6-(tert-Butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-6-chloro-pyridazine

The compound was prepared using the method in Example 26C using3,6-dichloropyridazine for 5-bromopyrimidine (63 mg, 32% yield). ¹H NMR(CD₃OD, 300 MHz), δ 8.63 (s, 1H), 8.37-8.33 d, J=9 Hz, 1H), 8.29-8.24(d, J=9 Hz, 1H), 8.09-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.89-7.79 (m,1H), 7.49-7.43 (m, 2H), 4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 0.87 (s,9H), −0.02 (s, 6H). MS (DCI-NH₃) [M+H]⁺ at 400.

Example 150B [6-(6-Chloro-pyridazin-3-yl)-naphthalen-2-yl]-methanol

The compound was prepared using the method in Example 26D using2[6-(tert-butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-6-chloro-pyridazinefor 5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine(29 mg, 68% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.63 (s, 1H), 8.37-8.33(d, J=9 Hz, 1H), 8.29-8.24 (d, J=9 Hz, 1H), 8.09-8.02 (m, 1H), 7.94-7.88(m, 1H), 7.89-7.79 (m, 1H), 7.49-7.43 (m, 2H), 4.1-3.94 (t, J=5.7 Hz,2H), 3.09-3.02 (t, J=5.7 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 271.

Example 150C Methanesulfonic acid6-(6-chloro-pyridazin-3-yl)-naphthalen-2-ylethyl ester

The title compound was prepared by the method of Example 3B, using theproduct from Example 150B in place of the product from Example 3A togive an off-white solid.

Example 150D3-Chloro-6-{6-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridazine

The title compound was prepared by the method of Example 3C using theproduct from Example 150C in place of the product from Example 3B (3.2mg, 16% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.63 (s, 1H), 8.37-8.33 d,J=9 Hz, 1H), 8.29-8.24 (d, J=9 Hz, 1H), 8.09-8.02 (m, 1H), 7.94-7.88 (m,1H), 7.89-7.79 (m, 1H), 7.49-7.43 (m, 2H), 3.24-3.28 (m, 1H), 3.12-3.01(m, 1H), 2.75-2.55 (m, 3H), 2.45-2.34 (m, 2H), 2.09-1.98 (m, 1H),1.91-1.78 (m, 2H), 1.56-1.41 (m, 1H), 1.19 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 352.

Example 1515-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidin-2-ylamineExample 151A5-[6-(tert-Butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-pyrimidin-2-ylamine

The compound was prepared using the method in Example 26C using2-amino-5-iodopyrimidine for 5-bromopyrimidine (85 mg, 46% yield). ¹HNMR (CD₃OD, 300 MHz), δ 8.79 (s, 2H), 8.1 (s, 1H), 7.98-7.95 (m, 2H),7.84 (s, 1H), 7.77-7.74 (d, J=6 Hz, 1H), 7.52-7.47 (d, J=6 Hz, 1H),4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 0.87 (s, 9H), −0.02 (s, 6H). MS(DCI-NH₃) [M+H]⁺ at 380.

Example 151B [6-(2-Amino-pyrimidin-5-yl)naphthalen-2-yl]-ethanol

The compound was prepared using the method in Example 26D using5-[6-(tert-butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-pyrimidin-2-ylaminefor 5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine(29 mg, 68% yield). ¹H NMR (CD₃OD, 300 MHz), δ 8.79 (s, 2H), 8.1 (s,1H), 7.98-7.95 (m, 2H), 7.84 (s, 1H), 7.77-7.74 (d, J=6 Hz, 1H),7.52-7.47 (d, J=6 Hz, 1H), 4.1-3.94 (t, J=5.7 Hz, 2H), 3.09-3.02 (t,J=5.7 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at 252.

Example 151C Methanesulfonic acid6-(2-amino-pyrimidin-5-yl)-naphthalen-2-ylethyl ester

The title compound was prepared by the method of Example 3B, using theproduct from Example 151B in place of the product from Example 3A togive an off-white solid.

Example 151D5-{6-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyrimidin-2-ylamine

The title compound was prepared by the method of Example 3C using theproduct from Example 151C in place of the product from Example 3B (5.4mg, 23% yield), ¹H NMR (CD₃OD, 300 MHz), δ 8.79 (s, 2H), 8.1 (s, 1H),7.98-7.95 (m, 2H), 7.84 (s, 1H), 7.77-7.74 (d, J=6 Hz, 1H), 7.52-7.47(d, J=6 Hz, 1H), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1H), 2.75-2.55 (m,3H), 2.45-2.34 (m, 2H), 2.09-1.98 (m, 1H), 1.91-1.78 (m, 2H), 1.56-1.41(m, 1H), 1.19 (d, J=6 Hz, 3H). MS (DCI-NH₃) [M+H]⁺ at 333.

Example 1522-Methyl-5-{6-[2-((2R)2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridineExample 152A5-[6-(tert-Butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-2-methyl-pyridine

The compound was prepared using the method in Example 26C using5-bromo-2-methylpyridine for 5-bromopyrimidine (61 mg, 26% yield). ¹HNMR (CD₃OD, 300 MHz), δ 9.13 (s, 1H), 9.88-9.84 (d, J=9, 1H), 8.35 (s,1H), 8.1-7.98 (m, 3H), 7.94-7.89 (m, 2H), 7.62-7.57 (d, J=6 Hz, 1H),4.96-4.86 (m, 2H), 3.03-2.91 (m, 2H), 2.66 (s, 3H), 0.87 (s, 9H), −0.02(s, 6H). MS (DCI-NH₃) [M+H]⁺ at 378.

Example 152B [6-(6-Methyl-pyridin-3-yl)naphthalen-2-yl]-ethanol

The compound was prepared by the method in Example 26D substituting5-[6-(tert-butyl-dimethyl-silanyloxyethyl)-naphthalen-2-yl]-2-methyl-pyridinein place of5-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-naphthyl]pyrimidine (29mg, 68% yield). ¹H NMR (CD₃OD, 300 MHz), δ 9.13 (s, 1H), 9.88-9.84 (d,J=9, 1H), 8.35 (s, 1H), 8.1-7.98 (m, 3H), 7.94-7.89 (m, 2H), 7.62-7.57(d, J=6 Hz, 1H), 4.1-3.94 (t, J=5.7 Hz, 2H), 3.09-3.02 (t, J=5.7 Hz,2H), 2.64 (s, 3H). MS (DCI-NH₃) [M+H]⁺ at 250.

Example 152C Methanesulfonic acid6-(6-methyl-pyridin-3-yl)-naphthalen-2-ylethyl ester

The title compound was prepared by the method of Example 3B, using theproduct from Example 152B in place of the product from Example 3A togive an off-white solid.

Example 152D2-Methyl-5-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-pyridine

The title compound was prepared by the method of Example 3C substitutingthe product from Example 152C in place of the product from Example 3B(4.8 mg, 17% yield). ¹H NMR (CD₃OD, 300 MHz), δ 9.13 (s, 1H), 9.88-9.84(d, J=9 Hz, 1H), 8.35 (s, 1H), 8.1-7.98 (m, 3H), 7.94-7.89 (m, 2H),7.62-7.57 (d, J=6 Hz, 1H), 3.24-3.28 (m, 1H), 3.12-3.01 (m, 1H), 2.84(s, 3H), 2.75-2.55 (m, 3H), 2.45-2.34 (m, 2H), 2.09-1.98 (m, 1H),1.91-1.78 (m, 2H), 1.56-1.41 (m, 1H), 1.19 (d, J=6 Hz, 3H). MS (DCI-NH₃)[M+H]⁺ at 331.

Example 153 3-Bromo-7-(2-pyrrolidin-1-yl-ethyl)[1,5]naphthyridineExample 153A 3,7-Dibromo-1,5-naphthyridine

To a stirred solution of 1.3 g (10 mmol) of 1,5-naphthyridine in 60 mLof CCl₄ was added 4.30 g (23 mmol) of bromine in 6 mL of CCl₄ and themixture was refluxed for 1 hr. Pyridine (0.79 g, 10 mmol) in 10 mL ofCCl₄ was added over a period of 0.5 hr to the refluxing mixture and themixture was heated for an additional 12 hr, cooled and filtered. Thedark green solid was treated with 100 mL of 10% solution of NaOH for 1hr and the resulting solution was extracted with chloroform. Thechloroform and the CCl₄ reaction solution were combined, dried overNa₂SO₄ filtered and evaporated under reduced pressure. The residue waschromatographed using 5% ethyl acetate in CCl₄ (25% yield). M.p.238-239° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.80 (m, 2H), 9.10 (m, 2H). MS(ESI) [M+H]⁺ at 288.

Example 153B Tributyl-(2-ethoxy-vinyl)-stannane

The title compound was prepared as described by Wollenberg et al J. Am.Chem. Soc. 1977, 99, 7365.

Example 153C 3-Bromo-7-(2-ethoxy-vinyl)-[1,5]naphthyridine

A solution of 3,7-dibromo-1,5-naphthyridine (0.5 g, 1.74 mmol),tributyl-2-ethoxy-vinylstannane (1.91 mmol, 0.69 g), LiCl (8.7 mmol,0.37 g) and 0.085 g of PdCl₂(PPh₃)₂ in 50 mL of toluene was heated at95° C. for 16 hr. After cooling off, 20 mL of a 2 M solution of KF wasadded to the mixture and stirring was continued for 0.5 hr. The mixturewas diluted with 100 mL of CH₂Cl₂ and washed successively with asaturated solution of sodium bicarbonate, brine and water. The organiclayer was dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was chromatographed using 5% MeOH inCH₂Cl₂ to give the desired material in 55% yield. ¹H NMR (CDCl₃, 300MHz) δ 1.40 (m, 3H), 4.05 (m, 2H), 5.85 (s, 1H), 7.25 (s, 1H), 8.15 (m,1H), 8.55 (m, 1H), 8.85 (m, 2H). MS (ESI) [M+H]⁺ at 280.

Example 153D (7-Bromo-[1,5]naphthyridin-3-yl)-acetaldehyde

To a mixture of the product from Example 153C (0.25 g, 0.89 mmol) in 15mL of THF was added 1.5 mL of HCl (6N). The mixture was heated to refluxfor 5 hr, cooled and the pH adjusted to 8.0 with NaOH. The mixture wasdiluted with 75 mL of CH₂Cl₂ and washed successively with a saturatedsolution of sodium bicarbonate, brine and water. The organic layer wasdried over sodium sulfate, filtered and evaporated under reducedpressure to give the desired product in 95% yield. ¹H NMR (CDCl₃, 300MHz) δ 3.75 (m, 2H), 8.25 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.00 (m,1H), 9.90 (s, 1H). MS (ESI) [M+H]⁺ at 252.

Example 153E 3-Bromo-7-(2-pyrrolidin-1-yl-ethyl)[1,5]naphthyridine

To a stirred solution of the product from Example 153D (0.1 g, 0.4mmol), acetic acid (0.4 mmol, 0.025 g) and pyrrolidine (0.44 mmol, 0.031g) in dry THF (5 ml) NaBH(OAc)₃ was added (0.6 mmol, 0.127 g). After 12hr at room temperature the mixture was diluted with 50 mL of CH₂Cl₂ andwashed successively with a saturated solution of sodium bicarbonate,brine and water. The organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedover silica using 10% MeOH in CH₂Cl₂. The desired compound was obtainedin 40%. ¹H NMR (CDCl₃, 300 MHz) δ 1.60 (m, 4H), 2.20 (m, 4H), 2.75 (m,4H), 8.30 (m, 1H), 8.40 (m, 1H), 8.90 (m, 1H), 9.05 (m, 1H). MS (ESI)[M+H]⁺ at 307.

Example 1543-Bromo-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine

The title compound was prepared by the method described in Example 153E,using (2R)-2-methylpyrrolidine in place of pyrrolidine. ¹H NMR (CDCl₃,300 MHz) δ 1.20 (d, J=7 Hz, 3H), 1.50 (m, 4H), 2.20 (m, 2H), 2.40 (m,1H), 2.60 (m, 2H), 2.75 (m, 2H), 8.25 (m, 1H), 8.45 (m, 1H), 8.85 (m,1H), 9.15 (m, 1H). MS (ESI) [M+H]⁺ at 321.

Example 155 3-Bromo-7-(2-piperidin-1-ylethyl)-[1,5]naphthyridine

The title compound was prepared by the method described in Example 153E,using piperidine in place of pyrrolidine. ¹H NMR (CDCl₃, 300 MHz) δ1.45-1.60 (m, 6H), 1.50 (m, 4H), 2.30 (m, 4H), 8.30 (m, 1H), 8.40 (m,1H), 8.95 (m, 1H), 9.10 (m, 1H). MS (ESI) [M+H]⁺ at 321.

Example 1563-(2,6-Dimethyl-pyridin-3-yl)-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine

The product from Example 154 (50 mg, 0.16 mmol),2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(0.21 mmol, 0.048 g), Pd(PPh₃)₂Cl₂ (0.007 g, 0.008 mmol), and 1 M Na₂CO₃(0.42 mL, 0.42 mmol) in isopropanol (5 mL) was heated to 90° C. under adry nitrogen atmosphere for 24 hr. After cooling, the reaction mixturewas filtered through diatomaceous earth and concentrated under reducedpressure. The crude material was purified by column chromatography usinga mixture of dichloromethane/methanol/NH₄OH (90:10:1) to afford theproduct (53% yield). ¹H NMR (DMSO-D₆, 300 MHz) δ 1.25 (d, J=7 Hz, 3H),1.55 (m, 2H), 1.60 (m, 2H), 2.25 (m, 2H), 2.35 (m, 1H), 2.50 (s, 3H),2.55 (s, 3H), 2.60-2.70 (m, 4H), 7.20 (m, 1H), 7.95 (m, 1H), 8.30 (m,1H), 8.70 (m, 1H), 8.90 (m, 1H), 9.25 (m, 1H). MS (ESI) [M+H]⁺ at 347.

Example 1573-(2,4-Dimethoxy-pyrimidin-5-yl)-7-[2-(2R-2-methyl-pyrrolidin-1-yl)-ethyl]-[1,5]naphthyridine

The title compound was prepared by the method described in Example 156,using 2,4-dimethoxypyrimidin-5-ylboronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CDCl₃, 300 MHz) δ 1.20 (d, J=7 Hz, 3H), 1.50 (m, 2H), 1.65 (m,2H), 2.20 (m, 2H), 2.35 (m, 1H), 2.65-2.70 (m, 4H), 3.85 (s, 6H), 8.30(m, 1H), 8.70 (m, 1H), 8.80 (s, 1H), 8.90 (m, 1H), 9.25 (m, 1H). MS(ESI) [M+H]⁺ at 380.

Example 1583-(2,6-Dimethyl-pyridin-3-yl)-7-(2-pyrrolidin-1-yl-ethyl)-[1,5]naphthyridine

The title compound was prepared by the method described in Example 156,using the product from Example 153E in place of the product from Example154. ¹H NMR (CDCl₃, 300 MHz) δ 1.55 (m, 4H), 2.35 (m, 4H), 2.50 (s, 3H),2.55 (s, 3H) 2.60-2.70 (m, 4H), 7.25 (m, 1H), 7.90 (m, 1H), 8.30 (m,1H), 8.70 (m, 1H), 8.90 (m, 1H), 9.25 (m, 1H). MS (ESI) [M+H]⁺ at 333.

Example 1593-(2,4-Dimethoxy-pyrimidin-5-yl)-7-(2-pyrrolidin-1-yl-ethyl)-[1,5]naphthyridine

The title compound was prepared by the method described in Example 156,using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product fromExample 153E in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridineand the product from Example 154. ¹H NMR (CDCl₃, 300 MHz) δ 1.55 (m,2H), 1.65 (m, 2H), 2.50 (m, 4H), 2.60-2.65 (m, 4H), 3.80 (s, 3H), 3.85(s, 3H), 8.35 (m, 1H), 8.70 (m, 1H), 8.85 (s, 1H), 8.90 (m, 1H), 9.20(m, 1H). MS (ESI) [M+H]⁺ at 366.

Example 1603-(2,6-Dimethyl-pyridin-3-yl)-7-(2-piperidin-1-yl-ethyl)-[1,5]naphthyridine

The title compound was prepared by the method described in Example 156,using the product from Example 155 in place of the product from Example154. ¹H NMR (CDCl₃, 300 MHz) δ 1.45-160 (m, 6H), 2.75 (m, 4H), 2.30 (s,3H), 2.35 (s, 3H) 2.55-2.65 (m, 4H), 7.20 (m, 1H), 7.95 (m, 1H), 8.20(m, 1H), 8.65 (m, 1H), 8.95 (m, 1H), 9.15 (m, 1H). MS (ESI) [M+H]⁺ at347.

Example 1613-(2,4-Dimethoxy-pyrimidin-5-yl)-7-(2-piperidin-1-yl-ethyl)-[1,5]naphthyridine

The title compound was prepared by the method described in Example 156,using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product fromExample 155 in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridineand the product from Example 154. ¹H NMR (CDCl₃, 300 MHz) δ 1.40-1.55(m, 6H), 2.45 (m, 4H), 2.65 (m, 4H), 3.70 (s, 3H), 3.80 (s, 3H), 8.35(m, 1H), 8.75 (m, 1H), 8.80 (s, 1H), 8.95 (m, 1H), 9.30 (m, 1H). MS(ESI) [M+H]⁺ at 380.

Example 1623-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-7-pyridin-4-yl-isoquinoline

The title compound was prepared by the method described in Example 62G,using 4-pyridineboronic acid in place of 2,6-difluoro-3-pyridineboronicacid. ¹H NMR (CDCl₃, 400 MHz) δ 9.29 (s, 1H), 8.71 (dd, 2H), 8.20 (d,1H), 7.93 (dd, 1H), 7.88 (d, J=8 Hz, 1H), 7.62-7.61 (m, 3H), 3.41-3.34(m, 2H), 3.28-3.25 (m, 2H), 2.84-2.79 (m, 1H), 2.79-2.69 (m, 1H),2.61-2.50 (m, 1H), 2.43-2.37 (m, 1H), 2.04-1.50 (m, 3H), 1.22 (m, 3H).¹³C NMR (CDCl₃, 400 MHz) δ 152.1, 150.1, 147.0, 136.1, 136.0, 128.7,127.0, 125.6, 121.4, 118.4, 60.8, 53.9, 46.2, 36.9, 32.7, 22.0, 18.7,10.4. MS (DCI-NH₃) [M+H]⁺ at 318.

Example 1637-(6-Methoxy-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline

The title compound was prepared by the method described in Example 62G,using 2-methoxy-5-pyridineboronic acid in place of2,6-difluoro-3-pyridineboronic acid. ¹H NMR (CDCl₃, 400 MHz) δ 9.24 (s,1H), 9.49 (d, J=3 Hz, 1H), 8.04 (s, 1H), 7.89 (dd, J=3, 12 Hz, 1H), 7.83(s, 2H), 7.55 (s, 1H), 6.87 (d, J=12 Hz, 1H), 4.01 (s, 3H), 3.35-3.15(m, 4H), 2.67-2.58 (m, 2H), 2.45-2.28 (m, 2H), 2.00-1.46 (m, 3H), 1.17(d, 3H). ¹³C NMR (CDCl₃, 400 MHz) δ 163.4, 151.8, 144.9, 137.1, 135.7,135.2, 129.1, 128.9, 127.2, 126.7, 124.3, 118.1, 110.9, 60.3, 54.1,53.8, 46.3, 37.2, 32.9, 22.0, 19.2. MS (DCI-NH₃) [M+H]⁺ at 347.

Example 1643-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-7-pyrimidin-5-yl-isoquinoline

The title compound was prepared by the method described in Example 62G,using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine inplace of 2,6-difluoro-3-pyridineboronic acid. ¹H NMR (CDCl₃, 400 MHz) δ9.29 (s, 1H), 9.26 (s, 1H), 9.07 (s, 2H), 8.15 (s, 1H), 7.93 (d, J=12Hz, 1H), 7.87 (dd, J=3, 12 Hz, 1H), 7.64 (s, 1H), 3.44-3.28 (m, 4H),2.91-2.41 (m, 3H), 2.07-1.54 (m, 4H), 1.30 (d, J=8 Hz, 3H). ¹³C NMR(CDCl₃, 400 MHz) δ 157.3, 154.6, 152.0, 135.9, 133.3, 132.2, 128.5,127.5, 127.0, 125.6, 118.5, 61.1, 53.9, 53.8, 36.7, 32.6, 21.9, 18.5. MS(DCI-NH₃) [M+H]⁺ at 319.

Example 1657-(6-Fluoro-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline

The title compound was prepared by the method described in Example 62G,using 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridinein place of 2,6-difluoro-3-pyridineboronic acid. ¹H NMR (CDCl₃, 400 MHz)δ 9.26 (s, 1H), 8.53 (m, 1H), 8.11-8.06 (m, 2H), 7.88 (d, J=8 Hz, 1H),7.84 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.06 (dd, J=4, 12 Hz, 1H), 3.40-3.26(m, 3H), 2.88-2.82 (m, 1H), 2.79-2.72 (m, 1H), 2.63-2.58 (m, 1H),2.46-2.39 (m, 1H), 2.06-1.52 (m, 4H), 1.27 (d, 3H). ¹³C NMR (CDCl₃, 400MHz) δ 164.0, 161.6, 153.2, 151.9, 145.7, 145.5, 139.5, 139.4, 135.5,134.5, 133.7, 133.6, 129.0, 127.0, 127.0, 125.2, 116.3, 109.7, 109.3,60.9, 53.8, 46.2, 36.7, 32.6, 21.9, 18.5. MS (DCI-NH₃) [M+H]⁺ at 336.

Example 1665-{3-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-isoquinolin-7-yl}-nicotinonitrile

The title compound was prepared by the method described in Example 62G,using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrilein place of 2,6-difluoro-3-pyridineboronic acid. ¹H NMR (CDCl₃, 400 MHz)δ 9.30 (s, 1H), 9.15 (d, J=2 Hz, 1H), 8.90 (d, J=2 Hz, 1H), 8.26 (m,1H), 8.16 (d, J=2 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 7.86 (dd, J=2, 12 Hz,1H), 7.65 (s, 1H), 3.44-3.29 (m, 3H), 2.93-2.88 (q, J=8 Hz, 1H),2.82-2.75 (m, 1H), 2.66-2.60 (m, 1H), 2.49-2.42 (m, 1H), 2.07-1.54 (m,4H), 1.29 (d, J=8 Hz, 3H). ¹³C NMR (CDCl₃, 400 MHz) δ 154.0, 152.0,151.0, 150.5, 136.9, 135.9, 135.7, 133.4, 128.5, 127.5, 126.9, 125.9,118.2, 116.1, 110.0, 61.0, 53.8, 53.7, 36.6, 32.5, 21.9, 18.2. MS(DCI-NH₃) [M+H]⁺ at 343.

Example 1677-(3-Chloro-pyridin-4-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline

The title compound was prepared by the method described in Example 62G,using 3-chloro-4-pyridineboronic acid in place of2,6-difluoro-3-pyridineboronic acid. ¹H NMR (CDCl₃, 400 MHz) δ 9.25, (s,1H), 8.72 (s, 1H), 8.57 (d, J=4 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=8 Hz,1H), 7.78 (dd, J=2, 12, Hz, 1H), 7.65 (s, 1H), 7.37 (d, J=4 Hz, 1H),3.47-3.27 (m, 4H), 2.87-2.47 (m, 3H), 2.08-1.60 (m, 4H), 1.31 (d, J=8Hz, 3H). ¹³C NMR (CDCl₃, 400 MHz) δ 153.4, 151.9, 149.6, 147.5, 146.1,135.7, 134.3, 130.4, 129.7, 127.6, 126.4, 126.0, 124.9, 118.4, 61.1,53.6, 53.5, 35.3, 35.0, 32.4, 32.3, 21.7, 18.1. MS (DCI-NH₃) [M+H]⁺ at352.

Example 1687-Bromo-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-4-olExample 168A 4-Bromo-1-iodo-2-nitro-benzene

NaNO₂ (0.83 g, 12.00 mmol) was gradually added to conc. H₂SO₄ (9 mL).The resulting mixture was stirred and heated to 70° C. for 15 minutesthen cooled to room temperature (r.t.). Next, 4-bromo-2-nitroaniline(2.4 g, 11.00 mmol) was dissolved in glacial acetic acid (22 mL) andadded dropwise to the HSO₃NO solution, while maintaining reactiontemperature below 40° C. After addition, the resulting mixture wasstirred at r.t. for 30 minutes and poured into a 70° C. solution of KI(2.0 g, 12.00 mmol) dissolved in 20 mL of water. The temperature wasmaintained while stirring for 20 minutes and then diluted with 150 mLwater and filtered. The precipitate was washed with 50 mL water anddried under vacuum to provide the product in 86% yield as an orangesolid, which was used without further purification. ¹H NMR (CDCl₃, 300MHz) δ 8.00 (d, J=3 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 7.42 (dd, J=3, 9 Hz,1H). MS (DCI-NH₃) [M+H]⁺ at 328.8.

Example 168B 5-Bromo-2-iodo-phenylamine

To a 15-18° C. stirred solution of SnCl₂ (5.20 g, 27.44 mmol), dissolvedin 10 mL conc. HCl, was quickly added a solution of Example 168A (1.8 g,5.49 mmol) in ethanol (14 mL). The resulting mixture was heated to 55°C. for 15 minutes, cooled in an ice bath, made basic by addition of asaturated KOH solution, and extracted with 250 mL CHCl₃. The organicphase was dried with Na₂SO₄, filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (100% hexanes to 50/50 hexanes/dichloromethane) toprovide the product as a white solid in 74% yield. ¹H NMR (CDCl₃, 300MHz) δ 7.47 (d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.62 (dd, J=3, 9 Hz,1H), 4.00 (bs, 1H). MS (DCI-NH₃) [M]⁺ at 297.

Example 168C5-Bromo-2-[4-((2R)-2-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine

A solution of Example 168B (0.2 g, 0.67 mmol),1-but-3-ynyl-(2R)-2-methyl-pyrrolidine (7.4 mL as a 0.1 M solution inacetonitrile, 0.74 mmol), and triethylamine (10 mL, 72.0 mmol) wasdegassed with nitrogen for 10 minutes while stirring at r.t. Next,Pd(PPh₃)₂Cl₂ (0.010 g, 0.013 mmol) and CuI (0.003 g, 0.013 mmol) wereadded and the resulting mixture was degassed for an additional 10minutes, sealed, and stirred at r.t. for 18 hours. Contents were thenconcentrated under reduced pressure and the residue was dissolved in 100mL dichloromethane, washed twice with each: 50 mL sat. NaHCO₃, 50 mLwater, and 50 mL brine, dried with Na₂SO₄, and concentrated underreduced pressure. The crude material was purified by columnchromatography (100% dichloromethane to 95:5 dichloromethane/methanol)to afford the product in 30% yield as a light yellow oil. ¹H NMR (CD₃OD,300 MHz) δ 7.03 (d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.68 (dd, J=3, 9Hz, 1H), 3.41-3.20 (m, 2H), 2.79-2.52 (m, 5H), 2.12-2.04 (m, 1H),1.92-1.82 (m, 2H), 1.56-1.47 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI)[M+H]⁺ at 308.

Example 168D7-Bromo-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-4-ol

To a mixture of Example 168C (0.10 g, 0.325 mmol) in 2 mL of water wasadded 1.5 mL 6 M HCl. The resulting solution was cooled to 0° C. andNaNO₂ (0.034 g, 0.488 mmol), dissolved in 1 mL water, was addeddropwise. The resulting mixture was stirred for 30 minutes at 0° C. andsubsequently heated to 90° C. for one hour. After cooling, contents werefiltered and the precipitate was washed with 10 mL water and dried underreduced pressure to provide the product in 47% yield as a brown solid inHCl salt form, which was used without further purification. ¹H NMR(CD₃OD, 300 MHz) δ 8.10 (d, J=9 Hz, 1H), 7.82 (d, J=3 Hz, 1H), 7.60 (dd,J=3, 9 Hz, 1H), 3.89-3.76 (m, 2H), 3.58-3.53 (m, 1H) 3.42-3.23 (m, 4H),2.38-2.30 (m, 1H), 2.16-2.06 (m, 2H), 1.83-1.75 (m, 1H), 1.51 (d, J=6Hz, 3H). MS (ESI) [M]⁺ at 336.

Example 1694-{3-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrileExample 169A 4-(2-Amino-4-bromo-phenyl)-but-3-yn-1-ol

The title compound was prepared using the procedure described in Example168C, using 3-butyn-1-ol instead of1-but-3-ynyl-(2R)-2-methyl-pyrrolidine. ¹H NMR (CD₃OD, 300 MHz) δ 7.03(d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.68 (dd, J=3, 9 Hz, 1H), 3.73(t, J=6 Hz, 2H), 2.65 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M]⁺ at 240 [M+NH₃]⁺at 257.

Example 169B 7-Bromo-3-(2-hydroxy-ethyl)-cinnolin-4-ol

The title compound was prepared by the method described in Example 168D,using the product from Example 169A in place of the product from Example168C. ¹H NMR (CD₃OD, 300 MHz) δ 8.07 (d, J=9 Hz, 1H), 7.77 (d, J=3 Hz,1H), 7.54 (dd, J=3, 9 Hz, 1H), 3.92 (t, J=6 Hz, 2H), 3.02 (t, J=6 Hz,2H). MS (DCI-NH₃) [M]⁺ at 269.

Example 169C 7-Bromo-4-chloro-3-(2-chloro-ethyl)-cinnoline

To a stirred mixture of the product from Example 169B (0.20 g, 0.744mmol) in chlorobenzene (5 mL) was added POCl₃ (0.10 mL, 1.11 mmol) andanhydrous pyridine (0.018 mL, 0.223 mmol). The resulting mixture washeated to 100° C. for 1 hour, cooled to r.t., and subsequentlyconcentrated under reduced pressure. The residue was neutralized with 10mL of a sat. K₂CO₃ solution, extracted twice with 25 mL dichloromethane,and concentrated. The crude material was purified by columnchromatography (50:50 hexanes/dichloromethane to 100% dichloromethane)to afford the product in 42% yield as a brown solid. ¹H NMR (CDCl₃, 300MHz) δ 8.14 (d, J=9 Hz, 1H), 7.54 (d, J=3 Hz, 1H), 7.49 (dd, J=3, 9 Hz,1H), 3.95 (t, J=6 Hz, 2H), 3.28 (t, J=6 Hz, 2H). MS (DCI-NH₃) [M+H]⁺ at307.

Example 169D 4-[3-(2-Chloro-ethyl)-cinnolin-7-yl]-benzonitrile

A mixture of the product from Example 169C (0.095 g, 0.312 mmol),4-cyanophenylboronic acid (0.046 g, 0.343 mmol), Pd(PPh₃)₂Cl₂ (0.011 g,0.016 mmol), and 1 M Na₂CO₃ (0.778 mL, 0.778 mmol) in de-gassedisopropanol/toluene (5 mL, 1:1) was heated to 90° C. under a drynitrogen atmosphere for 24 hours. After cooling, the reaction mixturewas diluted with 20 mL water, extracted twice with 25 mLdichloromethane, and concentrated under reduced pressure. The crudematerial was purified by column chromatography (100% dichloromethane to99:1 dichloromethane/methanol) to afford the product in 50% yield as abrown-orange solid. ¹H NMR (CDCl₃, 300 MHz) δ 8.76 (d, J=3 Hz, 1H), 8.02(dd, J=3, 9 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 7.87 (q, J=9 Hz, 4H), 7.80(s, 1H), 4.14 (t, J=6 Hz, 2H), 3.69 (t, J=6 Hz, 2H). MS (DCI-NH₃)[M-Cl]⁺ at 258, [M+H]⁺ at 294.

Example 169E4-{3-[2-((rac)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

Racemic 2-methylpyrrolidine (0.5 mL, neat) was added to the product fromExample 169D (0.01 g, 0.034 mmol) and heated to 65° C. in a sealed tubefor 18 hours. After cooling, the reaction mixture was concentrated underreduced pressure and purified by column chromatography (100%dichloromethane to 95:5 dichloromethane/methanol) to afford the productin 43% yield as a brown-yellow semi-solid. ¹H NMR (CD₃OD, 300 MHz) δ8.72 (m, 1H), 8.20 (dd, J=3, 9 Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=9 Hz,1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.58-3.46 (m, 4H),2.85-2.65 (m, 2H), 2.57-2.51 (m, 1H), 2.03-1.90 (m, 1H), 1.89-1.83 (m,2H), 1.56-1.50 (m, 1H), 1.21 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 343.

Example 1707-Bromo-4-chloro-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 169C,using the product from Example 168D in place of the product from Example169B. ¹H NMR (CD₃OD, 300 MHz) δ 8.69 (d, J=3 Hz, 1H), 8.21 (d, J=9 Hz,1H), 8.07 (dd, J=3, 9 Hz, 1H), 3.63-3.58 (m, 2H), 3.46-3.30 (m, 2H),2.73-2.64 (m, 1H), 2.55-2.42 (m, 2H), 2.06-1.95 (m, 1H), 1.84-1.77 (m,2H), 1.48-1.41 (m, 1H), 1.14 (d, J=6 Hz, 3H). MS (ESI) [M]⁺ at 354.

Example 1714-{4-Hydroxy-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

A mixture of the product from Example 168D (0.30 g, 0.805 mmol),4-cyanophenylboronic acid (0.15 g, 1.05 mmol), Pd(PPh₃)₂Cl₂ (0.03 g,0.04 mmol), and 1 M Na₂CO₃ (2.01 mL, 2.01 mmol) in isopropanol (15 mL)was heated to 90° C. under a dry nitrogen atmosphere for 2 days. Aftercooling, the reaction mixture was filtered through celite andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (100% dichloromethane to 90:10dichloromethane/methanol) to afford the product in 33% yield as a lightbrown solid. ¹H NMR (CD₃OD, 300 MHz) δ 8.29 (d, J=9 Hz, 1H), 7.95 (q,J=9 Hz, 4H), 7.83 (d, J=3 Hz, 1H), 7.75 (dd, J=3, 9 Hz, 1H), 3.49-3.42(m, 2H), 3.17-3.12 (m, 2H), 2.78-2.73 (m, 2H), 2.62-2.59 (m, 1H),2.12-2.09 (m, 1H), 1.92-1.84 (m, 2H), 1.61-1.53 (m, 1H), 1.25 (d, J=6Hz, 3H). MS (ESI) [M+H]⁺ at 359.

Example 1724-{4-Isopropoxy-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 171,using the product from Example 170 in place of the product from Example168D. ¹H NMR (CD₃OD, 300 MHz) δ 8.69 (d, J=3 Hz, 1H), 8.32 (d, J=9 Hz,1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.92, (d, J=9 Hz,2H), 4.88-4.77 (m, 1H), 3.71-3.49 (m, 4H), 3.06-2.91 (m, 2H), 2.81-2.73(m, 1H), 2.19-2.10 (m, 1H), 1.97-1.90 (m, 2H), 1.61-1.53 (m, 1H), 1.48(d, J=6 Hz, 6H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 401.

Example 1734-{3-[2-(4-Methyl-piperazin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 169E,using 1-methylpiperazine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD,300 MHz) δ 8.70 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.13 (s, 1H),8.11-8.01 (m, 3H), 7.91 (d, J=9 Hz, 2H), 3.44 (t, J=6 Hz, 2H), 2.95 (t,J=6 Hz, 2H), 2.75-2.45 (m, 8H), 2.28 (s, 3H). MS (ESI) [M+H]⁺ at 358.

Example 174 4-[3-(2-Piperidin-1-yl-ethyl)-cinnolin-7-yl]-benzonitrile

The title compound was prepared by the method described in Example 169E,using piperidine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD, 300MHz) δ 8.70 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.13 (s, 1H), 8.12-8.04(m, 3H), 7.91 (d, J=9 Hz, 2H), 3.44 (t, J=6 Hz, 2H), 2.91 (t, J=6 Hz,2H), 2.61 (m, 4H), 1.65 (m, 4H), 1.51 (m, 2H). MS (ESI) [M+H]⁺ at 343.

Example 175 4-[3-(2-Pyrrolidin-1-yl-ethyl)-cinnolin-7-yl]-benzonitrile

The title compound was prepared by the method described in Example 169E,using pyrrolidine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD, 300MHz) δ 8.71 (m, 1H), 8.20 (dd, J=3, 9 Hz, 1H), 8.15 (s, 1H), 8.11 (d,J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H), 3.50 (t, J=9Hz, 2H), 3.21 (t, J=9 Hz, 2H), 2.85 (m, 4H), 1.90 (m, 4H). MS (ESI)[M+H]⁺ at 329.

Example 1764-{3-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

(2R)-2-methylpyrrolidine (L)-tartrate (0.100 g, 0.425 mmol) waspartitioned between toluene (0.5 mL) and 5 M NaOH/brine (1:1, 1 mLtotal). The organic phase was then added to the product from Example169D (0.01 g, 0.034 mmol) and heated to 85° C. in a sealed tube for 48hours. After cooling, the reaction mixture was concentrated underreduced pressure and purified by column chromatography (100%dichloromethane to 95:5 dichloromethane/methanol) to afford the productin 27% yield as a yellow solid. ¹H NMR (CD₃OD, 300 MHz) δ 8.73 (m, 1H),8.21 (dd, J=3, 9 Hz, 1H), 8.14 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.06 (d,J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H), 3.72-3.48 (m, 4H), 3.15-2.90 (m, 2H),2.86-2.75 (m, 1H), 2.21-2.10 (m, 1H), 1.98-1.91 (m, 2H), 1.67-1.60 (m,1H), 1.31 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 343.

Example 1774-{3-[2-((2R)-2-Hydroxymethyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 169E,using pyrrolidin-(2R)-2-yl-methanol in place of 2-methylpyrrolidine. ¹HNMR (CD₃OD, 300 MHz) δ 8.71 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.15 (s,1H), 8.10 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H),3.58-3.43 (m, 4H), 2.92 (m, 1H), 2.73 (m, 1H), 2.48 (m, 1H), 2.01-1.92(m, 2H), 1.85-1.67 (m, 4H). MS (ESI) [M+H]⁺ at 359.

Example 178 4-[3-(2-Morpholin-4-yl-ethyl)-cinnolin-7-yl]-benzonitrile

The title compound was prepared by the method described in Example 169E,using morpholine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD, 300MHz) δ 8.70 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.14 (s, 1H), 8.10 (d,J=9 Hz, 1H), 8.05 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.70 (t, J=4.5Hz, 4H), 3.44 (t, J=9 Hz, 2H), 2.94 (t, J=9 Hz, 2H), 2.61 (t, J=4.5 Hz,4H). MS (ESI) [M+H]⁺ at 345.

Example 1794-{3-[2-(4-Methyl-piperidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 169E,using 4-methylpiperidine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD,300 MHz) δ 8.71 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.13 (s, 1H), 8.10(d, J=9 Hz, 1H), 8.05 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.47 (t,J=6 Hz, 2H), 3.14 (m, 2H), 3.00, (m, 2H), 2.26 (m, 2H), 1.73, (m, 2H),1.48-1.44 (m, 1H), 1.32-1.28 (m, 2H), 0.96 (d, J=6 Hz, 3H). MS (ESI)[M+H]⁺ at 357.

Example 1804-{3-[2-(Ethyl-methyl-amino)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 169E,using ethyl-methyl-amine in place of 2-methylpyrrolidine. ¹H NMR (CD₃OD,300 MHz) δ 8.70 (m, 1H), 8.19 (dd, J=3, 9 Hz, 1H), 8.13 (s, 1H), 8.10(d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.43 (t,J=6 Hz, 2H), 2.99 (t, J=6 Hz, 2H), 2.61 (q, J=9 Hz, 2H), 2.40 (s, 3H),1.12 (t, J=9 Hz, 3H). MS (ESI) [M+H]⁺ at 317.

Example 1817-(2,6-Dimethyl-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

A mixture of the product from Example 169C (0.100 g, 0.328 mmol),2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(0.077 g, 0.328 mmol), Pd(PPh₃)₂Cl₂ (0.012 g, 0.017 mmol), and 1 MNa₂CO₃ (0.820 mL, 0.820 mmol) in de-gassed isopropanol/toluene (5 mL,1:1) was heated to 90° C. under a dry nitrogen atmosphere for 24 hours.After cooling, the reaction mixture was filtered, diluted with 20 mLwater, extracted twice with 25 mL dichloromethane, and concentratedunder reduced pressure. Next, (2R)-2-methylpyrrolidine (L)-tartrate(0.100 g, 0.425 mmol) was partitioned between toluene (0.5 mL) and 5MNaOH/brine (1:1, 1 mL total). The toluene phase (0.5 mL) wassubsequently added to a solution of the above crude material inacetonitrile (3 mL) and the resulting mixture was heated to 85° C. in asealed tube for 48 hours. Upon cooling, the mixture was concentratedunder reduced pressure and purified by column chromatography (100%dichloromethane to 95:5 dichloromethane/methanol) to provide the titlecompound. ¹H NMR (CD₃OD, 300 MHz) δ 8.38 (m, 1H), 8.19 (s, 1H), 8.06 (d,J=9 Hz, 1H), 7.84 (dd, J=3, 9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.27 (d,J=9 Hz, 1H), 3.52-3.28 (m, 4H), 2.78-2.62 (m, 2H), 2.59 (s, 3H), 2.52(s, 3H), 2.46-2.39 (m, 1H), 2.08-1.98 (m, 1H), 1.86-1.78 (m, 2H),1.56-1.42 (m, 1H), 1.18 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 347.

Example 1827-(2,4-Dimethoxy-pyrimidin-5-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 2,4-dimethoxypyrimidine-5-boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.59 (m, 1H), 8.56 (s, 1H), 8.16 (s, 1H),8.06-8.00 (m, 2H), 4.12 (s, 3H), 4.08 (s, 3H), 3.58-3.38 (m, 4H),2.87-2.52 (m, 3H), 2.16-2.05 (m, 1H), 1.91-1.83 (m, 2H), 1.58-1.47 (m,1H), 1.22 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 380.

Example 1837-(6-Methoxy-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 2-methoxy-5-pyridine boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.64 (m, 2H), 8.23-7.98 (m, 3H), 8.12 (d, J=9Hz, 1H), 6.99 (d, J=9 Hz, 1H), 4.01 (s, 3H), 3.82-3.46 (m, 4H),3.26-3.20 (m, 2H), 3.04-2.98 (m, 1H), 2.38-2.24 (m, 1H), 2.17-2.04 (m,2H), 1.78-1.70 (m, 1H), 1.42 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 349.

Example 1843-{3-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-benzonitrile

The title compound was prepared by the method described in Example 181,using 3-cyanophenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.73 (m, 1H), 8.28-8.13 (m, 5H), 7.83 (dd,J=3, 9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 3.82-3.60 (m, 4H), 3.41-3.28 (m,2H), 3.18-3.06 (m, 1H), 2.36-2.21 (m, 1H), 2.13-2.02 (m, 2H), 1.78-1.71(m, 1H), 1.41 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 343.

Example 1855-{3-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-nicotinonitrile

The title compound was prepared by the method described in Example 181,using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrilein place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 9.36 (m, 1H), 9.03 (m, 1H), 8.84 (s, 1H), 8.78(m, 1H), 8.28-8.24 (m, 2H), 8.19 (d, J=9 Hz, 1H), 4.16-3.97 (m, 1H),3.82-3.57 (m, 5H), 3.38-3.26 (m, 1H), 2.41-2.32 (m, 1H), 2.29-2.17 (m,2H), 1.84-1.78 (m, 1H), 1.43 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 344.

Example 1867-(4-Fluoro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 4-fluorophenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.62 (m, 1H), 8.21-8.07 (m, 3H), 7.92-7.87 (m,2H), 7.33-7.25 (m, 2H), 4.03-3.95 (m, 1H), 3.83-3.53 (m, 5H), 3.07-2.99(m, 1H), 2.41-2.30 (m, 1H), 2.18-2.10 (m, 2H), 1.82-1.77 (m, 1H), 1.43(d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 336.

Example 1872-{3-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-pyrrole-1-carboxylicacid tert-butyl ester

The title compound was prepared by the method described in Example 181,using 1-(t-butoxycarbonyl)pyrrole-2-boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.36 (m, 1H), 8.19 (s, 1H), 7.96 (d, J=9 Hz,1H), 7.87 (dd, J=3, 9 Hz, 1H), 7.47 (m, 1H), 6.47 (m, 1H), 6.37 (m, 1H),4.03-3.95 (m, 1H), 3.82-3.51 (m, 5H), 3.27-3.23 (m, 1H), 2.38-2.27 (m,1H), 2.18-2.06 (m, 2H), 1.82-1.77 (m, 1H), 1.42 (d, J=6 Hz, 3H), 1.38(s, 9H). MS (ESI) [M+H]⁺ at 407.

Example 188(3-{3-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-cinnolin-7-yl}-phenyl)-methanol

The title compound was prepared by the method described in Example 181,using 3-(hydroxymethyl)phenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.62 (m, 1H), 8.19-8.03 (m, 3H), 7.83-7.76 (m,2H), 7.57-7.43 (m, 2H), 4.76 (s, 2H), 3.58-3.38 (m, 4H), 2.84-2.45 (m,3H), 2.12-2.02 (m, 1H), 1.92-1.82 (m, 2H), 1.57-1.46 (m, 1H), 1.21 (d,J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 348.

Example 1897-(3,5-Difluoro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 3,5-difluorophenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.60 (m, 1H), 8.22 (s, 1H), 8.10-8.03 (m, 2H),7.81-7.75 (m, 1H), 7.23-7.17 (m, 2H), 4.05-3.96 (m, 1H), 3.82-3.51 (m,5H), 3.27-3.23 (m, 1H), 2.38-2.27 (m, 1H), 2.18-2.06 (m, 2H), 1.82-1.77(m, 1H), 1.42 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 354.

Example 1903-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-7-thiophen-3-yl-cinnoline

The title compound was prepared by the method described in Example 181,using 3-thiophene boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.63 (m, 1H), 8.28 (dd, J=3, 9 Hz, 1H), 8.18(s, 1H), 8.05 (m, 2H), 7.76 (m, 1H), 7.63 (m, 1H), 4.05-3.96 (m, 1H),3.83-3.52 (m, 5H), 3.27-3.23 (m, 1H), 2.41-2.30 (m, 1H), 2.18-2.06 (m,2H), 1.83-1.77 (m, 1H), 1.43 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 324.

Example 1917-(4-Chloro-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 4-chlorophenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.64 (m, 1H), 8.21-8.06 (m, 3H), 7.88-7.82 (m,2H), 7.60-7.54 (m, 2H), 4.03-3.96 (m, 1H), 3.83-3.53 (m, 5H), 3.07-2.99(m, 1H), 2.41-2.30 (m, 1H), 2.18-2.09 (m, 2H), 1.82-1.76 (m, 1H), 1.44(d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 352.

Example 1927-(4-Ethoxy-phenyl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

The title compound was prepared by the method described in Example 181,using 4-ethoxyphenyl boronic acid in place of2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.¹H NMR (CD₃OD, 300 MHz) δ 8.59 (m, 1H), 8.21 (dd, J=3, 9 Hz, 1H), 8.18(s, 1H), 8.06 (d, J=9 Hz, 1H), 7.82-7.78 (m, 2H), 7.10-7.06 (m, 2H),4.14 (q, J=6 Hz, 2H), 4.05-3.97 (m, 1H), 3.83-3.55 (m, 5H), 3.07-2.98(m, 1H), 2.41-2.30 (m, 1H), 2.19-2.07 (m, 2H), 1.82-1.76 (m, 1H), 1.44(t, J=6 Hz, 3H), 1.41 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 362.

Example 1933-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-7-(1H-pyrrol-2-yl)-cinnoline

To a solution of the product from Example 187 (0.007 g, 0.017 mmol) intetrahydrofuran (2 mL), was added NaOMe (0.03 mL, 25% in methanol) andstirred at r.t. for 3 hours. The reaction mixture was then concentratedunder reduced pressure, re-dissolved in water (2 mL), extracted withethyl acetate (2 mL), dried with Na₂SO₄, and concentrated to afford theproduct in 76% yield as a yellowish solid. ¹H NMR (CD₃OD, 300 MHz) δ8.31 (m, 1H), 8.02 (dd, J=3, 9 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=9 Hz,1H), 6.89 (m, 1H), 6.71 (m, 1H), 6.18 (m, 1H), 3.33-3.19 (m, 4H),2.53-2.22 (m, 3H), 1.96-1.87 (m, 1H), 1.77-1.64 (m, 2H), 1.43-1.37 (m,1H), 1.06 (d, J=6 Hz, 3H). MS (ESI) [M+H]⁺ at 307.

Example 1942-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline

The title compound was prepared using the procedure described in Example57 using 1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanone (reference P. Schenoneet al., J. Heterocycl. Chem. 19, 1982, 1355-1361) for1-(1,3-thiazol-2-yl)-ethanone. ¹H NMR (300 MHz, CD₃OD) δ 1.20 (d, J=6Hz, 3H), 1.5 (m, 1H), 1.84 (m, 2H), 2.07 (m, 1H), 2.60 (m, 3H), 2.72 (s,3H), 3.05 (m, 2H), 3.23 (m, 1H), 3.35 (m, 1H), 3.1 (s, 3H), 7.64 (dd,J=9 Hz, J=3 Hz, 1H), 7.69 (d, J=9 Hz, 1 H), 7.73 (d, J=1.70 Hz, 1H),7.94 (d, J=9 Hz, 1H), 7.96 (d, J=1.70 Hz, 1H), 8.22 (d, J=9 Hz, 1H);(DCI/NH₃) m/z 335 (M+H)⁺.

Example 195 Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as histamine-3 receptor ligands (H₃ receptor ligands), thefollowing tests were conducted according to methods previously described(European Journal of Pharmacology, 188:219-227 (1990); Journal ofPharmacology and Experimental Therapeutics, 275:598-604 (1995); Journalof Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996); andBiochemical Pharmacology, 22:3099-3108 (1973)).

Briefly, male Sprague-Dawley rat brain cortices were homogenized (1 gtissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing proteaseinhibitor cocktail (Calbiochem) using a polytron set at 20,500 rpm.Homogenates were centrifuged for 20 minutes at 40,000×g. The supernatantwas decanted, and pellets were weighed. The pellet was resuspended bypolytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with proteaseinhibitors and centrifuged for 20 minutes at 40,000×g. The membranepellet was resuspended in 6.25 volumes (per gram wet weight of pellet)of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flashfrozen in liquid N₂ and stored at −70° C. until used in assays. Ratcortical membranes (12 mg wet weight/tube) were incubated with(³H)—N-α-methylhistamine (˜0.6 nM) with or without H₃ receptorantagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5mM EDTA (pH 7.7). Test compounds were dissolved in DMSO to provide a 20mM solution, serially diluted and then added to the incubation mixturesprior to initiating the incubation assay by addition of the membranes.Thioperamide (3 μM) was used to determine nonspecific binding. Bindingincubations were conducted for 30 minutes at 25° C. and terminated byaddition of 2 mL of ice cold 50 mM Tris-HCl (pH 7.7) and filtrationthrough 0.3% polyethylenimine-soaked Unifilter plates (Packard). Thesefilters were washed 4 additional times with 2 mL of ice-cold 50 mMTris-HCl and dried for 1 hour. Radioactivity was determined using liquidscintillation counting techniques. Results were analyzed by Hilltransformation and K values were determined using the Cheng-Prusoffequation.

Generally, representative compounds of the invention demonstratedbinding affinities in the above assay from about 810 nM to about 0.12nM. Preferred compounds of the invention bound to histamine-3 receptorswith binding affinities from about 100 nM to about 0.12 nM. Morepreferred compounds of the invention bound to histamine-3 receptors withbinding affinities from about 20 nM to about 0.12 nM.

Compounds of the invention are histamine-3 receptor ligands thatmodulate function of the histamine-3 receptor by altering the activityof the receptor. These compounds may be inverse agonists that inhibitthe basal activity of the receptor or they may be antagonists thatcompletely block the action of receptor-activating agonists. Thesecompounds may also be partial agonists that partially block or partiallyactivate the histamine-3 receptor receptor or they may be agonists thatactivate the receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of the formula:

or a pharmaceutically acceptable salt, ester, or amide thereof, wherein:Y and Y′ are each independently CH or CF; X, X′, Z and Z′ are eachindependently C; Z is N; one of R₁ and R₂ is selected from the groupconsisting of halogen, cyano, and L₂R₆; the other of R₁ and R₂ isselected from the group consisting of hydrogen, alkyl, alkoxy, aryl,cycloalkyl, halogen, cyano, and thioalkoxy; R₃ is selected from thegroup consisting of hydrogen, alkyl, alkoxy, halogen, cyano, andthioalkoxy; R_(3a) is absent; R_(3b) is selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, andthioalkoxy; R₄ and R₅ are each independently selected from the groupconsisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, and (NR_(A)R_(B))alkyl, or R₄ and R₅ taken togetherwith the nitrogen atom to which each is attached form a non-aromaticring of the formula:

R₆ is selected from the group consisting of aryl, heteroaryl,heterocycle, and cycloalkyl, wherein each R₆ is optionally substitutedwith 1, 2 or 3 substituents selected from the group consisting alkyl,cyano, halo, —NR_(A)R_(B), alkoxy, alkoxyimino, hydroxyalkyl,alkylcarbonyl, alkoxycarbonyl, (NR_(A)R_(B))carbonyl,cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy; R₇, R₈,R₉, and R₁₀ at each occurrence are each independently selected from thegroup consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl; orone of the pair R₇ and R₈ or the pair R₉ and R₁₀ is taken together toform a C₃-C₆ ring, wherein 0, 1, or 2 heteroatoms selected from O, N, orS replace a carbon atom in the ring; R₁₁, R₁₂, R₁₃, and R₁₄ are eachindependently selected from the group consisting of hydrogen, hydroxy,hydroxyalkyl, alkyl, and fluoro; Q is selected from the group consistingof a bond, O, S, and NR₁₅; L is —[C(R₁₆)(R₁₇)]_(n)— or—[C(R₁₆)(R₁₇)]_(p)O—; L₂ is selected from the group consisting of abond, —O—, —C(═O)—, —S—, —[C(R₁₈)(R₁₉)]_(q)—, —O—[C(R₁₈)(R₁₉)]_(q)—,—NH— and —N(alkyl)-; R₁₅ is selected from the group consisting ofhydrogen, alkyl, acyl, amido, and formyl; R₁₆ and R₁₇ at each occurrenceare independently selected from the group consisting of hydrogen, alkyl,alkoxy, and fluoro; R₁₈ and R₁₉ at each occurrence are eachindependently selected from the group consisting of hydrogen, hydroxy,alkyl, alkoxy, and fluoro; R_(x) and R_(y) at each occurrence areindependently selected from the group consisting of hydrogen, hydroxy,alkyl, alkoxy, alkylamino, dialkylamino, and fluoro, or one of R_(x) orR_(y) represents a covalent bond when taken together with R_(x) or R_(y)on an adjacent carbon atom such that a double bond is representedbetween the adjacent carbon atoms; m is an integer from 1 to 5; n is aninteger from 1 to 6; p is an integer from 2 to 6; and q is an integerfrom 1 to
 4. 2. The compound of claim 1, wherein R₁ is bromo, cyano, orL₂R₆.
 3. The compound of claim 1, wherein R₁ is L₂R₆, L₂ is —CH(OH)—,—C(═O)—, or a bond, and R₆ is aryl, heteroaryl, heterocycle, orcycloalkyl, wherein each R₆ is optionally substituted with 1, 2 or 3substituents selected from the group consisting of alkyl, cyano, halo,—NR_(A)R_(B), alkoxy, alkoxyimino, hydroxyalkyl, alkylcarbonyl,alkoxycarbonyl, (NR_(A)R_(B))carbonyl, cycloalkylcarbonyl, alkylsulfonylhaloalkyl, and thioalkoxy.
 4. The compound of claim 1, wherein R₁ isL₂R₆, L₂ is a bond, and R₆ is aryl wherein the aryl is phenylsubstituted with 0, 1, or 2 substituents selected from the groupconsisting of cyano, halogen, —NR_(A)R_(B), alkoxy, hydroxyalkyl,alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, alkylsulfonyl,haloalkyl, and thioalkoxy.
 5. The compound of claim 1, wherein R₁ isL₂R₆, L₂ is a bond, and R₆ is selected from the group consisting offuryl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinonyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl,thienyl, triazinyl, and triazolyl, substituted with 0, 1, 2, or 3substituents selected from the group consisting of —NR_(A)R_(B),halogen, alkyl, cyano, alkoxyimino, alkoxycarbonyl,(NR_(A)R_(B))carbonyl, alkylcarbonyl, haloalkyl, and alkoxy.
 6. Thecompound of claim 1, wherein R₁ is L₂R₆, L₂ is a bond, and R₆ isselected from the group consisting of azepanyl, azetidinyl, aziridinyl,azocanyl, dihydrothiazolyl, morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl, pyrrolinyl, thiomorpholinyl, tetrahydropyridinyl,tetrahydrofuryl, and tetrahydropyranyl.
 7. The compound of claim 1,wherein R₄ and R₅ are each independently selected from methyl, ethyl,and propyl.
 8. The compound of claim 1, wherein R₄ and R₅ taken togetherwith the nitrogen atom to which each is attached form a 4- to 8-memberednon-aromatic ring represented by formula (a).
 9. The compound of claim8, wherein the 4- to 8-membered non-aromatic ring is selected from thegroup consisting of azetidinyl, azepanyl, azepinyl, pyrrolidinyl,pyrrolinyl, piperidinyl, piperazinyl, and tetrahydropyridinyl,substituted with 0, 1, or 2 substituents selected from the groupconsisting of alkyl, hydroxyalkyl, fluoroalkyl, and —NR_(A)R_(B). 10.The compound of claim 8, wherein at least one substituent represented byR₇, R₈, R₉, and R₁₀ is selected from the group consisting of alkyl,halogen, fluoroalkyl, and hydroxyalkyl or at least one substituentrepresented by R_(x) or R_(y) is selected from the group consisting ofhydrogen, hydroxy, and fluoro.
 11. The compound of claim 8, wherein the4- to 8-membered non-aromatic ring is selected from the group consistingof methylpyrrolidinyl, ethylpyrrolidinyl, dimethylaminopyrrolidinyl,isopropylpyrrolidinyl, isobutylpyrrolidinyl, hydroxymethylpyrrolidinyl,and fluoromethylpyrrolidinyl.
 12. The compound of claim 1, wherein R₄and R₅ taken together with the nitrogen atom to which each is attachedform morpholinyl or thiomorpholinyl.
 13. The compound of claim 1,wherein at least one substituent represented by R₇, R₈, R₉, and R₁₀ ishydroxyalkyl, fluoroalkyl, or alkyl.
 14. The compound of claim 1,wherein at least one substituent represented by R₇, R₈, R₉, and R₁₀ ismethyl, ethyl, fluoromethyl, or hydroxymethyl.
 15. The compound of claim1, wherein one substituent represented by R₇, R₈, R₉, and R₁₀ is alkyland the other three substituents are hydrogen.
 16. The compound of claim1, wherein R₁₁, R₁₂, R₁₃, and R₁₄ are each hydrogen.
 17. The compound ofclaim 1, wherein R₁₁ and R₁₂ each are hydrogen, and R₁₃ and R₁₄ are eachindependently selected from the group consisting of hydrogen and alkyl.18. The compound of claim 1, wherein R₁₅ is selected from the groupconsisting of hydrogen, alkyl, amido, and formyl.
 19. The compound ofclaim 1, wherein R₁₆ and R₁₇ are hydrogen.
 20. The compound of claim 1,wherein R₁₈ and R₁₉ are hydrogen.
 21. The compound of claim 1, wherein mis 2 or
 3. 22. The compound of claim 1, wherein n is 2 or
 3. 23. Thecompound of claim 1, wherein p is
 2. 24. The compound of claim 1,wherein q is
 1. 25. The compound of claim 1, selected from the groupconsisting of4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile;3-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile;7-(2,6-difluoro-3-pyridinyl)-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline;3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-(3-pyridinyl)isoquinoline;3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-7-pyridin-4-yl-isoquinoline;7-(6-methoxy-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline;3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-7-pyrimidin-5-yl-isoquinoline;5-{3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinolin-7-yl}-nicotinonitrile;7-(6-fluoro-pyridin-3-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline;and7-(3-chloro-pyridin-4-yl)-3-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-isoquinoline.26. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 27. A method of treating a condition or disordermodulated by the histamine-3 receptors in a mammal comprisingadministering an effective amount of a compound of claim 1, wherein thecondition or disorder is Alzheimer's disease, attention-deficithyperactivity disorder or schizophrenia.